Deposition of the C4d complement degradation product has been shown to be a marker of antibody-mediated rejection of solid organ allografts, including kidney, heart, liver, and lung. We investigated whether C4d deposition also would be useful in monitoring rejection in human composite tissue allografts. A total of 60 mucocutaneous formalin-fixed, paraffin-embedded and four frozen biopsy specimens from four patients with composite tissue allografts (three hands, one face) taken during a period of 7 days to 7 years after graft were immunostained for C4d by an immunoperoxidase and an immunofluorescence technique, respectively. C4d deposition was not found in any of the specimens studied, even though several of them showed pathological signs of rejection. No human leukocyte antigen alloantibodies were detected in any of the patients during the study period. These results suggest that humoral rejection occurs rarely, if at all, in the setting of human composite tissue allografts.