Since first reports in April 2009, the 2009 pandemic influenza A (H1N1) virus has spread around the world. The pandemic virus is antigenically distinct from seasonal influenza A (H1N1) viruses targeted by seasonal influenza vaccines. Results from recent serologic studies have suggested that seasonal influenza vaccines are unlikely to provide substantial cross-protection against infection with the pandemic H1N1 virus. However, how serologic results correlate with the complex immune responses that confer clinical protection remains uncertain. To complement the serologic studies and evaluate the effectiveness of 2008-09 trivalent seasonal influenza vaccine against laboratory-confirmed pandemic influenza A (H1N1) illness, CDC used available data to conduct a case-cohort analysis. The analysis used surveillance reports from eight states of persons aged >18 years with confirmed pandemic H1N1 illness during May-June 2009. Influenza vaccination coverage estimates for these states during the 2008-09 influenza season (September 2008-February 2009) were estimated for the population cohort by using preliminary Behavioral Risk Factor Surveillance Survey (BRFSS) data. The overall vaccine effectiveness (VE) against pandemic virus illness after adjustment for age group and presence of chronic medical conditions that increase the risk for complications from influenza was -10% (95% confidence interval [CI] = -43%-15%). Current evidence from this study and other studies does not suggest that seasonal influenza vaccination either decreases of increases the risk for acquiring pandemic H1N1 illness. To prevent seasonal and pandemic influenza, CDC recommends vaccination with seasonal and pandemic influenza vaccines.