['To determine, in serial fixed-flexion (FF) radiographs of subjects with knee osteoarthritis (KOA), the importance of, and basis for, the effect of alignment of the medial tibial plateau (MTP), as determined by the inter-margin distance (IMD), on joint space narrowing (JSN).', 'Baseline and 12-month X-rays of 590 knees with Kellgren and Lawrence grade (KLG) 2/3 OA from the public-release dataset of the Osteoarthritis Initiative (OAI) were assigned to subgroups based upon IMD at baseline (IMD(BL)) and the difference between IMD(BL) and IMD(12 mos). Relationships of JSN to IMD(BL) and to the difference between IMD(BL and) IMD(12 mos) were evaluated.', 'In all 590 knees, mean JSN was 0.13 ± 0.51 mm (P<0.0001) and MTP alignment and replication of IMD(BL) in the 12-month film were, in general, poor. JSN was significantly (P=0.012) more rapid in Subgroup A (IMD≤1.70 mm at both time points) than in Subgroup B (both IMDs>1.70 mm): 0.15 ± 0.43; 0.08 ± 0.47. Within Subgroup B we identified a subset, Subgroup B1, in which, although alignment was poor at both time points, the large IMD(BL) was, by chance, highly reproduced by IMD(12 mos) (difference between the two IMDs=0.01 ± 0.27 mm, NS). JSN in Subgroup B1 was 0.06 ± 0.41 mm and did not differ from that in other knees of Subgroup B (P=0.87). The standardized response mean (SRM) in all 590 knees and Subgroups A, B and B1 was 0.25, 0.34, 0.17 and 0.06, respectively. Independent of IMD(BL), JSN correlated significantly with the difference between the IMDs in the two radiographs (r=0.17, P=0.0001).'] Does alignment of the medial tibial plateau affect the rate of joint space narrowing in the osteoarthritic knee?