We evaluated whether the increased immunogenicity provided by an MF59-adjuvant influenza vaccine translates into increased protection among the elderly. Residents of 25 long-term care facilities received either the adjuvant or a non-adjuvant vaccine. The odds ratios (OR) of influenza-like illness were calculated for non-adjuvant vs. adjuvant vaccine recipients, also stratifying for chronic cardiovascular, respiratory, and renal diseases. The risk was higher for the non-adjuvant vaccine recipients and highest for those with respiratory disease (OR 2.27, 95% CI 1.09-4.82) and cardiovascular disease (OR 1.88; 95% CI 1.31-2.72). In this study the MF59-adjuvant vaccine provided superior clinical protection among the elderly, especially those with chronic diseases.