To date, an examination of the longitudinal relationship between perceived stress and C-reactive protein (CRP) is limited. We explored the relationship between perceived stress and CRP concurrently and across 2 and 4 years in 383 men and women. Multiple linear regressions examined the cross-sectional and longitudinal relationships between baseline stress and counter-stress scores with CRP at baseline, 2 years after baseline and 4 years after baseline, while controlling for covariates (age, smoking status, anti-inflammatory use, oral contraceptive use, physical activity, menopausal status, years since onset of menopause, post-menopausal hormone use and body mass index). Results indicate that stress and counter-stress were not related to CRP in either men or women at study baseline or 2 years later. Across a 4-year time frame, higher stress values were related to higher CRP values in women, but not men. Counter-stress was not related to CRP values in men or women across the 4 years. This study highlights the importance of examining the cross-sectional and longitudinal relationship between perceived stress and inflammation separately in men and women. Copyright © 2013 John Wiley & Sons, Ltd.