Our objective was to ascertain the nature of the associations between C-reactive protein (CRP) and cognition, and to examine how they are affected by gender and obesity. We evaluated 62 females and 63 males between 42 and 82 years of age. There were 20 lean females with a body mass index (BMI) of <25 kg/m2 and 42 overweight or obese females, with BMIs ≥25 kg/m2. There were 14 lean males and 49 with BMIs ≥25 kg/m2. CRP was associated with lower scores on cognitive tests of frontal lobe function among females and these associations were driven by the overweight/obese female group. In these data no associations between CRP and cognition were found among males. Obesity-associated inflammation is much more prominent in females and it appears to be associated with cognitive dysfunction, particularly of frontal lobe tasks.