Influenza type A viruses are endemic in aquatic birds but can cross the species barrier to infect the human respiratory tract. While transmission from birds to humans is rare, the introduction of novel avian influenza viruses into immunologically naïve human populations has significant pandemic potential. Avian influenza viruses are adapted for growth at 40uC, the temperature of the avian enteric tract. However, the human proximal airways, the likely site of initial inoculation by influenza viruses, are maintained at a cooler temperature (32uC), suggesting that zoonotic transmission may be limited by temperature differences between the two hosts. Using an in vitro model of human ciliated airway epithelium, we show that avian influenza viruses grow well at 37uC, a temperature reflective of distal airways, but are restricted for infection at 32uC. A panel of genetically manipulated human influenza viruses possessing avian or avian-like surface glycoproteins were also restricted at 32uC, but not 37uC, suggesting that avian virus glycoproteins are not adapted for efficient infection at the temperature of the proximal airways. Thus, avian influenza virus infection is restricted in the human proximal airways due to the cooler temperature of this region, thus limiting the likelihood of zoonotic and subsequent human-to-human transmission of these viruses. culture surface. Figure 1B indicates that substantial increases in AK levels, indicative of the onset of CPE, are first detected at 48 hrs pi for A/Victoria/3/75 at 32uC and 37uC and A/Dk/ Eng/62 at 37uC. This induction of AK coincided with peak viral titer for these viruses under these conditions (compare Figure 1A and 1B) and suggested that the loss of titer correlated with the onset of CPE. Increasing levels of AK between 48 and 96 hrs pi were directly associated with continually decreasing viral titers, further supporting this claim.