The adamantanes, amantadine and rimantadine, have been used as first-choice antiviral drugs against community outbreaks of influenza A viruses for many years. Rates of viruses resistant to these drugs have been increasing globally. Rapid surveillance for the emergence and spread of resistant viruses has become critical for appropriate treatment of patients. OBJECTIVE: To investigate the frequency of adamantane-resistant influenza A viruses circulating in the United States during the initial months of the 2005-2006 influenza season. DESIGN AND SETTING: Influenza isolates collected from 26 states from October 1 through December 31, 2005, and submitted to the US Centers for Disease Control and Prevention were tested for drug resistance as part of ongoing surveillance. Isolates were submitted from World Health Organization collaborating laboratories and National Respiratory and Enteric Virus Surveillance System laboratories. MAIN OUTCOME MEASURES: Using pyrosequencing and confirmatory assays, we identified viruses containing mutations within the M2 gene that are known to confer resistance to both amantadine and rimantadine. RESULTS: A total of 209 influenza A(H3N2) viruses isolated from patients in 26 states were screened, of which 193 (92.3%) contained a change at amino acid 31 (serine to asparagine [S31N]) in the M2 gene known to be correlated with adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same mutation. Drug-resistant viruses were distributed across the United States. CONCLUSIONS: The high proportion of influenza A viruses currently circulating in the United States demonstrating adamantane resistance highlights the clinical importance of rapid surveillance for antiviral resistance. Our results indicate that these drugs should not be used for the treatment or prophylaxis of influenza in the United States until susceptibility to adamantanes has been reestablished among circulating influenza A isolates.