BACKGROUND: Prioritizing the maintenance of healthy cognitive aging and personalizing preventive interventions to enhance their effectiveness is crucial as the global population ages. Systemic inflammation and depression in older people have been associated with decreased levels of cognition but results have been inconsistent. AIMS: To explore the interactive network of inflammation, depression and cognition by sex in older people. METHODS: We used novel network analysis to explore the unique associations between inflammatory biomarkers, depression, cognition, and somatic, genetic, and lifestyle risk factors in an older (aged 70-90 years), non-demented, community-dwelling sample from the longitudinal Sydney Memory and Aging Study (N = 916) at baseline and at a two-year follow-up. RESULTS: The networks of biomarkers, depression, cognition, and relevant covariates were significantly different between males and females. A stable negative link between depression and cognition was found in females only; a stable positive association between biomarker interleukin-6 and depression was found in females only; and a stable positive association between biomarker interleukin-8 and alcohol was found in females only. For both males and females, a stable, positive relationship was found between the presence of APOE-ε4 gene and biomarker C-reactive protein; between education and cognition; and between biomarker interleukin-6 and all other biomarkers. CONCLUSIONS: These findings suggest different psychophysiological mechanisms underlie the interactive network of biomarkers, depression and cognition in males and females that should be considered when designing personalized preventive interventions to maintain cognitively healthy aging.