Adamantanes have been used for the prophylaxis and treatment of Influenza A virus (IAV) infections worldwide. However, they have limited use because of increasing number of resistant viruses during recent years. In investigating the frequency of amantadine-resistant IAVs (H3N2) circulating in Iran in 2005-2008, we found that M2 sequences of recently circulating viruses that were amantadine-resistant contained a Ser31Asn mutation. Thus, adamantanes should not be used for treatment of prophylaxis of recent IAVs (H3N2) infections. In future, their potential use will depend on the resistance of circulating viruses.