BACKGROUND: Perceived stress and coping strategies may influence the risk of cardiovascular disease through their possible association with inflammation, but data remain controversial for perceived stress or scanty for coping strategies. PURPOSE: We examined the associations of perceived stress and coping strategies with serum high-sensitivity C-reactive protein (CRP) in a Japanese general population. METHODS: This cross-sectional study included 2,971 men and 4,902 women aged 40-69 years who were enrolled between 2005 and 2007. Subjects with possible inflammation-related disease, CRP levels ≥3,000 ng/mL, or currently used analgesics or lipid-lowering drugs were excluded. Analyses were performed by gender with adjustment for lifestyle, socioeconomic, and psychosocial factors. RESULTS: Unexpectedly, elevated perceived stress was significantly associated with lower CRP levels in men (P trend < 0.001) but not in women (P trend = 0.90) after adjustment for age and covariates. Among five items of coping strategies evaluated, "disengagement" showed a significant inverse association with CRP in men only (P trend = 0.027). In addition, a possible interaction between "emotional support seeking" and perceived stress on CRP was detected in men (P interaction = 0.021); "emotional support seeking" was associated with lower CRP at the high stress level only (P trend = 0.028). CONCLUSIONS: Both perceived stress and coping strategies may be associated with systemic inflammation in Japanese men, yet caution must be exercised before accepting the stress-inflammation-disease pathway.