Total lymphoid irradiation (TLI) is a novel type of adjuvant immunosuppression for patients who undergo cardiac transplantation and have refractory allograft rejection during standard immunosuppressive therapy. TLI consists of 6 to 10 fractions of 80 cGy (1 cGy = 1 rad) of irradiation to lymphatic tissues with use of the standard mantle and inverted Y fields. We have used TLI in six patients with biopsy-proven rejection that was refractory to standard treatments, including cyclosporine, azathioprine, antilymphocyte antibodies, and corticosteroids. In five patients, recalcitrant rejection was resolved after completion of TLI, and resolution persisted during long-term follow-up (17 to 30 months; mean, 22.2 months). In each patient, a substantial increase in the CD8 (suppressor T-lymphocyte) subset and elimination of B lymphocytes were demonstrated, findings that also persisted. Side effects were mild and primarily limited to transient leukopenia. In four patients, a readily treated cytomegalovirus reactivation was noted during TLI; thus, a causal relationship was suggested. In recipients of cardiac allografts who have refractory rejection, TLI provides long-lasting amelioration of the rejection profile. This result may be attributable to a relative enhancement of the suppressor T-cell subset and elimination of the B-lymphocyte line. Side effects are minimal, but monitoring for cytomegalovirus activation or reactivation is recommended.