A retrospective, clinical, epidemiologic, and risk-factor analysis was performed on 21 recipients of cardiac allografts who had experienced nocardiosis since the inception of the cardiac transplantation program at Stanford University Medical Center in 1968. The lung was the primary and only detectable site of infection in 17 (81%) of 21 patients, and there were three cases of disseminated disease. Presenting symptoms were either nonspecific (dry cough and fever) or absent (in 40%). The time of onset of infection following transplantation was variable (range, 43-982 days), and there was no period of peak incidence. Epidemiologic and risk-factor analysis failed to identify a nosocomial point-source or specific parameters that predisposed a patient to nocardial infection. Nocardiosis was not associated with the onset of primary infection with cytomegalovirus following transplantation. However, an association between pulmonary nocardiosis and subsequent development of nontuberculous mycobacteriosis was established in five of the 21 patients. All patients with nocardiosis were treated primarily with sulfisoxazole (6-12 g per day) for a mean of 13.2 months. No deaths were attributable to nocardial infection, nor could acquisition of the infection be shown to affect overall survival. The results of the study support an aggressive approach to diagnosis of infections in the immunocompromised host and suggest that a favorable therapeutic outcome may be anticipated in such individuals who sustain nocardiosis if the diagnosis is made early in the course of the infection and if appropriate antimicrobial therapy is instituted.