Background. C-reactive protein (CRP) is a non-specific marker of inflammation that has been associated with depression and vascular disease, particularly in men. This study aimed to investigate the association between high CRP concentration and depression while taking physical health into account.Method. A cross-sectional study of a community-dwelling sample of 5438 men aged 70+. Participants with scores >=,7 on the 15-item Geriatric Depression Scale (GDS- 15) were considered to display clinically significant depressive symptoms. We measured the serum concentration of CRP with a high-sensitivity assay. The assessment of physical co-morbidity included three components: the Charlson weighted index, self-report of major health events on a standardized questionnaire, and the physical component of the 36-item Short-Form Health Survey (SF-36). Other measured factors included age, native language, education, a standardized socio-economic index, smoking, prior or current history of depression treatment, cognitive impairment (Mini-Mental State Examination score <24) and body mass index (BMI).Results. Participants with depression (n = 340) were older than their controls without depression (age in years: 76.6 +/- 4.4 v. 75.4 +/- 4.1). Men with CRP concentration >3 mg/1 had an increased odds ratio (OR) [1.59, 95 % confidence interval (CI) 1.20-2.11] of being depressed compared to men with CRP <= 3 mg/1. This association became non-significant once we adjusted the analysis for the measures of physical co-morbidity and other confounding factors (OR 1.22, 95 % CI 0.86-1.73).Conclusions. The physiological mechanisms that lead to the onset and maintenance of depressive symptoms in older men remain to be determined, but CRP concentration is unlikely to play a significant role in that process.