Limited evidence of association between C-reactive protein levels and cardiovascular disease has been produced for Japanese whose median protein levels are low by western standards.We conducted a nested case-control study as part of the Japan Collaborative Cohort Study for evaluation of cancer risk (JACC Study). A total of 39,242 subjects 40–79 years of age provided serum samples at baseline between 1988 and 1990. During the 13-year follow-up, there were 525 deaths from total strokes (ICD10: I60–I69), 209 coronary heart diseases (I20–I25) and 939 total cardiovascular diseases (I00–I99). The control subjects were matched for sex, age, area of residence and year of serum storage, and analyses were conducted after further adjustment for cardiovascular risk factors. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured with ultra-sensitive latex-enhanced immunoassay.Median hs-CRP levels for controls were 0.40mg/L for men and 0.41mg/L for women. Hs-CRP levels were positively associated with risks of mortality from stroke, coronary heart disease, and total cardiovascular disease for men. The respective multivariable odds ratios (OR 95% CI) for the highest (≥0.85mg/L) vs. lowest (<0.19mg/L) quartiles of hs-CRP for men were 1.60 (0.90–2.85), 3.68 (1.02–13.3), and 2.31 (1.49–3.59). For women, positive associations with hs-CRP levels were weaker, reaching statistical significance only for total cardiovascular disease: OR=1.69 (1.06–2.68). The positive association with total cardiovascular disease did not vary according to sex, age, smoking status, or body mass index.Higher serum hs-CRP levels were associated with higher mortality from cardiovascular disease in Japanese.