Examine the joint effect of cognitive function and C-reactive protein (CRP) on all-cause mortality risk in older U.S. adults.Sample included 1335 older adult (≥60 years of age) participants in the 1999-2002 National Health and Nutrition Examination Survey. A four-level variable was created using cognitive function and CRP concentration. Mortality was assessed using National Center for Health Statistics linked death records from the National Death Index.Increased risk of all-cause mortality was revealed in adults with high CRP and low cognitive function and in those with low to average CRP and low cognitive function (P < .0001 for both). Sex-stratified analyses revealed increased all-cause mortality risk in males with low cognitive function, independent of CRP concentration. However, in females, a significant increase in all-cause mortality risk was only observed in those with low to average CRP and low cognitive function.Low cognitive function was associated with increased all-cause mortality risk independent of CRP concentration. However, the joint effect of cognitive function and CRP on all-cause mortality risk differed according to sex.