We evaluated the effectiveness of the 2010-2011 seasonal influenza vaccine for preventing laboratory-confirmed influenza in a South Korean population. A retrospective case-control study was conducted among patients who visited selected hospitals from September 2010 to May 2011. A total of 483 laboratory-confirmed influenza patients were included in the analysis as case subjects. For each case patient, two types of control patients were chosen at a ratio of 1:1:1, and 966 control subjects were selected. Vaccine effectiveness (VE) was defined as 100 × (1 - odds ratio for influenza in vaccinated versus nonvaccinated persons). The VE of the 2010-2011 seasonal influenza vaccine was 49.5% to 45.8% for both influenza A and B viruses and 50.8% to 47.2% for influenza A virus, according to the control type. The age-specific adjusted VE was 50.8% to 46.5% among subjects aged 19 to 49 years and 58.7% to 63.3% among those aged 50 to 64 years, according to the control type. Statistically significant VE was not found among those aged ≥65 years or against influenza B virus. The 2010-2011 seasonal influenza vaccine was effective for preventing laboratory-confirmed influenza, especially for influenza A virus, in a South Korean population. Evidence of the effectiveness of the influenza vaccine in older adults or against influenza B virus was not found.