Background: Medical staff's knowledge and preparedness has an important role in providing specialized care to the patients as well as controlling and preventing the epidemics. Objectives: The aim of the study is to examine and compare the knowledge and preparedness in terms of avian influenza (AI) among the first year medical students (FYMS) and interns of Tehran University of Medical Sciences, Tehran, Iran. Materials and Methods: A cross-sectional study was carried out on FYMS (n = 158) and interns (n = 158) in 2008. The data collected through a questionnaire, including 38 questions in two parts. The three statements were considered as follows: "true", "false" and "I do not know" for knowledge part and "yes", "no" and "I do not know" for preparedness part. We used the Chi-squared and Fisher's exact tests for the analysis. Results: 145 FYMS (91.8%) and 140 interns (88.6%) affirmed that not only AI afflict wild birds (P = 0.002). 139 FYMS (88%) but 128 interns (81%) also noted that AI virus can be transmitted from birds to humans. 144 FYMS (91.1%) and 140 interns (88.6%) held frequent hand washing is effective in preventing the disease (P < 0.001). 153 FYMS (96.8%) and 149 interns (94.3%) did not participate in training classes regarding AI (P = 0.132). 138 FYMS (87.3%) and 140 interns (88.6%) did not take human flu vaccine (P = 0.035). 143 FYMS (90.5%) and 133 interns (84.2%) believed they were not prepared for AI pandemics (P = 0.014). Conclusions: Although the general knowledge of our study groups on AI is relatively fair, they are not prepared for AI epidemics.Keywords: Influenza in Birds; Disease Outbreaks; Knowledge; Students, Medical; Civil Defense Implication for health policy/practice/research/medical education: Medical students are not well prepared against avian influenza epidemics and it is an urge for our health care system to amend the defects.