Objective. Depression has been associated with increased cardiovascular disease risk, and a depression-related elevation of high sensitivity C-reactive protein (hs-CRP) has been proposed as a possible mechanism. The objective of this paper is to examine association between depression and high sensitivity C-reactive protein (hs-CRP). Methods. Subjects consisted of 508 healthy adults (mean age 48.5 years; 49% women, 88% white) residing in central Massachusetts. Data were collected at baseline and at quarterly intervals over a one-year period per individual. Multivariable linear mixed models were used to assess the association for the entire sample and by gender. Results. The mean Beck Depression Inventory score was 5.8 (standard deviation (SD) 5.4; median 4.3), and average serum hs-CRP was 1.8 mg/L (SD 1.7; median 1.2). Results from the multivariable linear mixed models show that individuals with higher depression scores have higher levels of hs-CRP. Analyses by gender show persistence of an independent association among women, but not among men. Body mass index (BMI = weight(kg)/height(m)(2)) appears to be a partial mediator of this relationship. Conclusion. Depression score was correlated to hs-CRP levels in women. Further studies are required to elucidate the biological mechanisms underlying these associations and their implications.