The authors conducted a follow-up study of the association between mediastinal irradiation, chemotherapy, and mortality from coronary artery disease in 4665 patients treated for Hodgkin's disease. Study subjects were followed after the diagnosis of Hodgkin's disease until death or the closing date of the study. The average duration of follow-up was 7 years; 2415 patients died, and 124 cases of coronary artery disease were identified from death certificates, including 68 cases of acute myocardial infarction. The age-adjusted relative risks (RR) of death with any coronary artery disease after mediastinal irradiation and after chemotherapy were 1.87 (95% confidence interval [CI], 0.92 to 3.80) and 1.28 (CI, 0.77 to 2.15), respectively. A significantly increased risk of death in the subcategory myocardial infarction was observed after mediastinal irradiation (RR, 2.56; CI, 1.11 to 5.93) but not after chemotherapy (RR, 0. 97; CI, 0.53 to 1.77). These results support the hypothesis that radiation therapy to the mediastinum increases the risk of coronary artery disease.