Here, we report the diversity of amantadine-resistant mutants among avian influenza A viruses with pandemic potential (H5, H6, H7, and H9 hemagglutinin subtypes). Drug-resistant variants were not detected among 1979--83 isolates, whereas 31.1% of H5 and 10.6% of H9 strains from Southeast Asia isolated in 2000-04 carried mutations in M2 protein. In North America, resistant variants occurred among H7 viruses only (16.4% of those tested). H6 viruses were amantadine-sensitive. These findings prompt concern regarding the control of pandemic influenza, the possibility that the next pandemic virus will be amantadine-resistant and the need to monitor the use of the drug in poultry.