retina. Vitreous levels of VEGF progressively increase with more advanced retinopathy and are greatest in eyes with PDR and least in eyes from non-diabetic individuals or diabetics without DR (Adamis et al 1994; Aiello et al 1994). A reduc- tion of vitreous VEGF levels has been documented with PRP (Aiello et al 1994). VEGF levels have also been correlated with degree of macular edema, as determined by degree of leakage with ﬂuorescein angiography and central retinal thickness by OCT imaging (Funatsu et al 2006). A prospective, double-masked clinical trial using pegaptanib sodium (Macugen, Eyetech), an aptamer that inhibits VEGF 165 isoform, for DME has been completed. (Cunningham et al 2005) One-hundred and seventy-two patients with DME and BCVA between 20/50 and 20/320 were randomized to receive 0.3 mg, 1 mg, or 3 mg intravitreal pegaptanib injections or sham injections. Treatments were given at study entry, six weeks, and twelve weeks followed by additional injections with or without FML as needed for another 18 weeks. At the end of the 36-week trial, subjects in the 0.3 mg pegaptanib group had improved median BCVA (20/50 versus 20/63 in the sham group), and more eyes gained 10 letters (24% vs. 10%) and 15 letters (18% vs. 7%). Mean central retinal thickness as determined by OCT decreased by 68 um, while it decreased by only 4 um in the control group. Photocoagulation was deemed necessary in 25% of pegaptanib-treated eyes, while 48% of the control eyes received FML. No additional beneﬁt was seen with the higher doses of pegaptanib. The pegaptanib treatment was well tolerated, with only one case of culture-negative endophthalmitis reported. Further analysis examined the effects of VEGF-inhibition on PDR. Sixteen eyes in this study group had proliferative diabetic retinopathy at study entry. Of the 13 eyes in the pegaptanib treatment arm, eight (62%) showed regression of neovascularization based on fundus photography or ﬂuorescein angiography. Of the 4 fellow eyes and 3 eyes from the control group with baseline neovascularization that were examined, none showed regression. Further evidence for a direct effect on proliferative changes from diabetic retinopathy was the progression in 3 of the eight eyes which had regressed on pegaptanib therapy at week 52 after discontinuing pegaptanib at week 30. Ranibizumab (Lucentis, Genentech) is a neutralizing antibody targeted against all isoforms of VEGF which is FDA-approved for the intravitreal treatment of all subtypes of neovascular AMD. In a nonrandomized pilot study of ten patients, eyes with chronic DME received intraocular injections of 0.5 mg ranibizumab at study entry and at Clinical Ophthalmology 2008:2(2) Diabetic retinopathy 1, 2, 4, and 6 months (Chun et al 2006). At 7 months, mean visual acuity improved from 20/80 to 20/40 and mean foveal thickness decreased from 503 um to 246 um. No adverse events, including increase in foveal capillary nonperfusion, were reported. Bevacizumab (Avastin, Genentech) is a humanized pan- VEGF inhibiting antibody approved for colorectal cancer therapy. Whereas ranibizumab consists only of the Fc com- ponent of the antibody, bevacizumab is the full antibody and is not FDA-approved for intraocular use. A prospective examination of 51 eyes with DME that received one or two injections of bevacizumab with 6 to 12 week follow-up has been reported (Haritoglou et al 2006). Mean retinal thickness decreased from 541 um to 417 um at 6 weeks and to 377 um at 12 weeks. However, a statistically-signiﬁcant improvement in visual acuity was only seen at the 6 week time point. Fur- ther analysis showed that baseline visual acuity was the only predictive factor for an increase in visual acuity after 6 weeks of treatment. A more pronounced effect was reported in a retrospective analysis of 78 eyes with DME treated with 1 to 3 intravitreal injections of bevacizumab (1.25 mg or 2.5 mg) (Arevalo et al 2007). Bevacizumab-treated eyes showed a decrease in mean retinal thickness, stabilization of visual acuity in 41% of eyes, and a 2 line improvement in 55% of patients after 6 months of follow-up. Regression of iris, retinal and optic disc neovascular- ization clinically and angiographically after intravitreal administration of bevacizumab has been shown in a large retrospective case series, although eventual reperfusion of the neovascular fronds was documented in several cases (Avery et al 2006). In some cases, the effects of VEGF-inhibition on PDR was seen as soon as 24 hours after treatment. Although not substantiated by randomized controlled trials, reduc- tion in the caliber and fragility of neovascular lesions with anti-VEGF agents may decrease intraoperative hemorrhage during anterior and posterior segment surgery in the setting of PDR (Chen and Park 2006; Krzystolik et al 2006). Other approaches to modulate intraocular VEGF activity are being investigated. Intraocular injection of a VEGF- neutralizing anti-sense oligonucleotide has shown regression of ischemia-induced iris neovascularization in an animal model (Bhisitkul et al 2005). The VEGF trap (Regeneron, Bayer) is a soluble decoy VEGF receptor currently under investigation in the treatment of colorectal cancer (Konner and Dupont 2004). It consists of the binding domains of VEGF receptors 1 and 2, fused to the Fc fragment of IgG with a signiﬁcantly higher binding afﬁnity than monoclonal antibodies such as bevacizumab and ranibizumab for 429