OBJECTIVES: To evaluate the response to pandemic vaccination and seasonal and pandemic vaccine effectiveness (VE) in an Italian adult population, during the 2009-2010 influenza season. METHODS: Data were recorded by interviewing 19,275 subjects (≥35 years), randomly recruited from the general population of the Moli-sani project. Events [influenza-like illness (ILI), hospitalization and death], which had occurred between 1 November 2009 and 31 January 2010 were considered. VE was analyzed by multivariable Poisson regression analysis. RESULTS: Pandemic vaccine coverage was very low (2.4%) in subjects at high-flu risk, aged 35-65 years (N = 8,048); there was no significant preventive effect of vaccine against ILI. Seasonal vaccine coverage was 26.6% in the whole population (63% in elderly and 21.9% in middle-aged subjects at high-flu risk). There was a higher risk to develop ILI in middle-age [VE: -17% (95% CI: -35,-1)] or at high flu-risk [VE: -17% (95% CI: -39, 2)] vaccinated groups. CONCLUSIONS: Coverage of pandemic vaccine was very low in a Southern Italy population, with no protective effect against ILI.