Objective The aim of this cross-sectional descriptive study was to evaluate Iranian physicians' perception of generic medicines and evaluate its relationship with their demographic characteristics, as well as some other underlying factors. Methods A self-administered questionnaire was used to evaluate the perceptions of physicians in Iran with regard to generic medicines. The questionnaire included three general questions covering physicians' beliefs and attitudes toward generic substitution, and 18 questions relating to physicians' perceptions about generic medicines with regard to their efficacy, safety, cost containment, patient acceptance, marketing, and the role of government. Respondents' demographic characteristics and other background data were also collected. Results The analysis of 410 completed questionnaires indicated that [70 % of Iranian physicians prefer to prescribe generic medicines if they are assured that the generic products are equivalent to the brand name drugs. However, they do not believe that the safety and efficacy of generic and brand medicines are equivalent, especially when the medicine is produced domestically. Moreover, physicians mostly disagreed with the right of pharmacists to substitute generic medicines. According to the six dimensions of the administered questionnaire, the most important factor affecting the prescribing of generics is the government's efforts in sharing evidence and training the public, followed by cost containment size, beliefs in the efficacy and safety of generic medicines, patient acceptance and marketing activities. Conclusion In Iran, physicians, the main decision makers regarding drug selection, do not have positive perceptions relating to the efficacy and safety of generic medicines, especially with regard to domestically produced generics. Therefore, the government appears to have a very critical role in informing the public and health professionals on the safety and efficacy of generic medicines.