During a 4-year experience with cardiac transplantation, 33 hearts were obtained by autopsy or surgical resection for retransplantation. Arteritis was a feature common to all rejected hearts (14 of 14), but was absent in explanted hearts without rejection (0 of 19) (p = 0.001). Monitoring of acute cardiac rejection by endomyocardial biopsy (863 biopsies) was also reviewed, with special reference to the incidence of arteritis. Among the 16 patients with arteritis on 1 or more biopsies, 44% (7 patients, confidence limits 29 to 60%) suffered fatal rejection or underwent retransplantation because of irreversible rejection. Arteritis was seen in the small vessels obtained by endomyocardial biopsy in 4 of 5 persons who underwent biopsy within 3 days of death or retransplantation due to rejection and on none of the 6 persons who underwent biopsy within 3 days of death or retransplantation for causes other than rejection. Thus, arteritis is an important indicator for severe acute rejection, and although often reversible, may identify patients at higher risk for fatal rejection. Arteritis occurred in transplanted hearts subjected to varying combinations of cyclosporine, azathioprine and steroid therapy and could not be correlated with any drug regimen.