It has been suggested that one of the mechanisms of action of cyclosporin is by abrogation of major histocompatibility complex class II expression. We have tested this hypothesis by following the expression of DR7, a polymorphic determinant of the class II DR locus in cardiac biopsies from 12 heart or heart-lung recipients who were themselves DR7 negative but whose donors were DR7 positive. All patients received cyclosporine and azathioprine immunosuppression. Immunoperoxidase and immunofluorescent techniques were used. The DR7 determinant was found on interstitial structures on donor heart at all times studied, including at 2 years after transplantation. Double immunofluorescent labeling of donor heart before transplantation revealed that more than 60% of the DR7 was on endothelial cells. At later times the proportion of DR7 on endothelial cells increased, but even at 1 year some DR7 was found on interstitial structures not of endothelial origin. The significance of these findings to mechanisms of long-term immunosuppression is discussed.