We defined a cohort of people with major chronic conditions (152,585 subjects) in Navarre, Spain, using electronic records from physicians, to obtain 2010/11 mid-season estimates of influenza vaccine effectiveness. The adjusted estimates of the effectiveness of the 2010/11 trivalent influenza vaccine were 31% (95% confidence interval (CI): 20–40%) in preventing medically attended influenza-like illness, and 58% (95% CI: 11–80%) in preventing laboratory-confirmed influenza. Having received the monovalent influenza A(H1N1)2009 vaccine in the 2009/10 season had an independent preventive effect against medically attended influenza-like illness (17%, 95% CI: 1–30%), and having received both vaccines had 68% (95% CI: 23–87%) effectiveness in preventing laboratory-confirmed influenza.