This study examined the effect of congestive heart failure (CHF) on immune responses to influenza vaccination (2000-2001 preparation) in three groups of older adults including healthy, Class II and Class III/IV CHF. Serum antibody titers measured by hemagglutination inhibition (HI), and interferon-gamma (IFN-gamma), interleukin-10 (IL-10) and granzyme B (GrzB) levels in ex vivo virus-activated mononuclear cell cultures showed significant responses from pre-vaccination to 4 and 12 weeks post-vaccination (P<0.01). There was a trend for lower GrzB and higher IFN-gamma and IL-10 levels in healthy versus CHF groups (P<0.06) for all viral strains at 4 weeks. HI titers did not differ between groups. In the regression model, Grz B levels were significantly predicted by the IFN-gamma:IL-10 ratio and performance on the 6 min Walk Test; age and CHF dropped out of the model. In conclusion, CHF in older adults predicts GrzB responses to influenza vaccination due to cytokine and physical ability differences.