The relation between erythrocyte sedimentation rate (ESR) and risk of developing coronary heart disease (CHD) or fatal cerebrovascular accident was assessed in a cohort of 7,988 men and 8,685 women who participated in The Reykjavik Study (Iceland). Cardiovascular risk assessment was based on characteristics at baseline, from 1967 to 1996. During an average follow-up of 19 and 20 years, 2,092 men and 801 women, respectively, developed CHD, and 251 men and 178 women died from cerebrovascular accident. For men, the fully adjusted increase in risk of developing CHD predicted by the top compared with the bottom quintile of ESR was 57% (hazard ratio = 1.57, 95% confidence interval: 1.38, 1.78; p < 0.001); for women, risk was increased by 49% (hazard ratio = 1.49, 95% confidence interval: 1.16, 1.90; p < 0.001). The increased risk after baseline ESR measurement was stable for up to 25 years for men and 20 years for women. The fully adjusted risk of death due to stroke predicted by increasing the ln(ESR + 1) by one standard deviation was increased by 15% for men (p = 0.06) and 16% for women (p = 0.08). In conclusion, ESR is a long-term independent predictor of CHD in both men and women. These findings support the evidence of an inflammatory process in atherosclerosis.