Recombinant human erythropoietin is widely used in chronic dialysis patients. However, the long-term effect, especially on the incidence of cardiovascular disease, has not been critically evaluated. We observed the annual incidence of stroke and acute myocardial infarction from April 1988 through March 1993 in Okinawa, Japan. Until April 1990, erythropoietin was not generally used. Therefore, we have two periods: pre-erythropoietin, April 1988 through March 1990, and post-erythropoietin, April 1990 through March 1993. Two thousand one hundred and sixteen patients (1,219 males and 897 females) were on chronic dialysis during the study period by March 31, 1993. Every case of stroke and acute myocardial infarction during the study period was registered. The odds ratio was calculated using the data of the general population in each sex and age class obtained in the same area. A total of 86 cases of stroke and 15 cases of acute myocardial infarction were registered during the study period. The annual incidence, per 1,000 patient-years, of stroke was 12.5 (1988), 10.5 (1989), 12.7 (1990), 14.0 (1991), and 17.5 (1992). The incidence of stroke was increased in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.22 and 95% confidence interval (95% CI 1.06-1.41, p < 0.01). The annual incidence of acute myocardial infarction was 1.0 (1988), 1.8 (1989), 0.8 (1990), 2.9 (1991) and 4.7 (1992). The incidence of acute myocardial infarction was increased significantly in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.87 (95% CI 1.66-2.10, p < 0.01). The odds ratio of stroke to the general population was 4.25 (95% CI 3.10-5.82) in the pre-erythropoietin and 4.58 (95% CI 2.14-9.80) in the post-erythropoietin period. In acute myocardial infarction, it was 2.98 (95% CI 2.84-3.12) and 3.81 (95% CI 3.18-4.56). The odds ratio of acute myocardial infarction was significantly increased (p < 0.01). The introduction of erythropoietin was associated with an increased risk of cardiovascular disease, especially acute myocardial infarction. Erythropoietin may unmask the sclerotic lesion in chronic dialysis patients.