The development of acute rejection and coronary artery disease (CAD) was studied in 173 patients who survived at least 1 year after orthotopic heart transplantation. There were 20 late deaths. The incidence of acute rejection found on endomyocardial biopsies after 1 year was 5.6%. Alteration in the immunosuppressive regimen accounted for 77% of the rejection episodes (chi-square = 9.3, F less than 0.01). Acute rejection without alteration in immunosuppressive therapy occurred only 1.4% of the time. CAD developed in 28 patients (16.2%). The prevalence of CAD was 5.8% at 1 year, 15.5% at 2 years, and increased to 66% at 6 years. Patients developing CAD had 0.5 (+/- 0.8) rejection episodes after 1 year as opposed to 0.2 (+/- 0.5) rejection episodes in patients with no CAD (S1 less than 0.01 by Mann-Whitney). There was no difference in the number of rejection episodes during the first year. The total number of rejection episodes was 1.9 (+/- 1.6) and 1.2 (+/- 1.2) in patients with and without CAD, respectively (S1 less than 0.03 by Mann-Whitney). Diabetes mellitus was present in 25% of patients with CAD and 16.5% of patients without CAD (chi-square = 3.14, F less than 0.1). Acute rejection rarely occurs after 1 year and is usually caused by an alteration in the immunosuppressive regimen. CAD develops with increasing frequency and is correlated with rejection episodes and diabetes mellitus.