The absolute concentration of circulating lymphoblasts and prelymphoblasts has been shown repeatedly to closely correlate with acute cardiac rejection in heart transplant recipients. Little information, however, is available with respect to the reliability of this measurement in the late postoperative course. Fifty-two heart transplant recipient operated on from October 1985 through September 1986 were studied with cytoimmunologic monitoring for lymphocyte activation in peripheral blood. Immunosuppressive therapy consisted of azathioprine, cyclosporine, and steroids. Endomyocardial biopsies were obtained at regular intervals. Cytoimmunologic monitoring was performed daily during hospitalization and together with endomyocardial biopsy at outpatient visits. A total of 768 endomyocardial biopsies and 1077 mononuclear concentrates for study of lymphocyte activation were obtained. Concentration of activated cells showed a significant increase during acute rejection. Cytoimmunologic monitoring had an overall sensitivity of 76% and a specificity of 79%. Within 90 days after transplantation cytoimmunologic monitoring showed a sensitivity of 84%, which decreased to 71% beyond 3 months. We therefore conclude that cytoimmunologic monitoring, a noninvasive adjunct for diagnosis of acute allograft rejection, cannot replace routine endomyocardial biopsy, particularly in view of a significant loss in sensitivity in the late postoperative course.