Initial testing of the 2009 pandemic influenza A (H1N1) virus found it susceptible to neuraminidase inhibitors (oseltamivir and zanamivir) and resistant to adamantanes (amantadine and rimantadine). Neuraminidase inhibitors have been used widely for treatment and chemoprophylaxis of 2009 pandemic influenza A (H1N1); however, sporadic cases of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection have been reported worldwide, including nine U.S. cases identified as of September 4. On July 14, CDC was contacted by a physician at a summer camp in North Carolina regarding two cases of influenza-like illness (ILI) in adolescent girls receiving oseltamivir chemoprophylaxis during an ILI outbreak that had begun June 18. The two girls stayed in the same cabin, and both received oseltamivir during a mass chemoprophylaxis program in which approximately 600 campers and staff members received oseltamivir or zanamivir. On July 20 and July 22, the North Carolina State Laboratory of Public Health confirmed pandemic H1N1 virus infection in respiratory specimens from both girls. On August 14 and August 19, CDC detected the H275Y mutation (N1 numbering) in neuraminidase from both specimens by pyrosequencing. The H275Y mutation is associated with resistance to oseltamivir; zanamivir susceptibility is retained. A second mutation (I223V) in neuraminidase also was detected in both specimens. This is the first report of oseltamivir resistance in pandemic H1N1 cases with an epidemiologic link. Health-care providers should be aware that antiviral resistance can develop during chemoprophylaxis or treatment with subtherapeutic dosages and should follow published recommendations for antiviral medications.