The high-density lipoprotein (HDL) constituent apolipoprotein CI (apoCI) protects mice against mortality in bacterial sepsis. We assessed whether high plasma apoCI levels protect against mortality from infection in humans. We determined plasma levels of apoCI, lipids, and C-reactive protein in 85-year-old participants of the prospective population-based Leiden 85-Plus Study (n = 561). Participants were followed for specific causes of death. High apoCI levels were associated with 40% reduced risk of mortality from infection (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42-0.86; p =.005) for every increase of 1 standard deviation in apoCI level. A similar association was observed for high HDL cholesterol (HR, 0.65; 95% CI, 0.46-0.94; p =.022), but not for LDL cholesterol, triglycerides, and C-reactive protein levels. The association of apoCI was independent of HDL cholesterol, as multivariate analysis did not alter the association for apoCI (HR, 0.63; 95% CI, 0.44-0.90; p =.013), whereas for HDL cholesterol significance was lost. We conclude that high apoCI levels are associated with reduced mortality from infection, in line with experimental evidence in rodents.