Activation of proinflammatory cytokines is associated with depressed mood, feelings of fatigue, and changes in cognitive function. This study examined the relationships between cognitive performance and circulating cellular markers of inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP), in moderately depressed and comparison healthy older adults. We conducted a cross-sectional analysis of 87 volunteers (45 nondepressed and 42 depressed) in which participants completed the Structured Clinical Diagnostic Interview and were evaluated by a geriatric psychiatrist for dementia, depression, stroke risk, and neurologic disorders. Volunteers also completed an electrocardiogram, standard battery of laboratory tests, and neuropsychological examination that assessed memory functions of Encoding and Recall, Executive Function, and Attention/Processing. Mid-morning IL-6 and CRP levels were assessed. The data analysis showed that Encoding and Recall were inversely associated with IL-6 across diagnostic groups after controlling for chronological age, Mini-Mental State Examination, body mass index, literacy level, depression severity, and sex. CRP was not associated with cognition. Depression status was associated with recall independent of IL-6 levels. In conclusion, IL-6 serum levels among elderly individuals is a significant correlate of memory performance. Women, in particular, appear sensitive to IL-6 fluctuations across diagnostic groups. © 2012 American Association for Geriatric Psychiatry.