1 The most recent generation of immunosuppressive agents targets the calcineurin signaling pathway of T cells and is thus directed primarily at the cellular component of allograft rejection. The recognition of transplanted organs as foreign is mediated by complex immunologic pathways, which, in general terms, can be divided into cellular (especially T-cellвЂ“mediated) and humoral (or antibody-mediated) pathways. Our data show C4d is unlikely to have utility in small intestine allograft biopsy specimens however, further study in liver allografts, in conjunction with donor-specific antibody testing, is warranted. C4d stained the endothelium in a subset of explanted liver allografts with ductopenic rejection or chronic vascular rejection and strongly stained 1 explant with features of hyperacute rejection.Д¬onclusions.-The clinical utility of C4d staining in solid organ transplantation may vary by organ. In liver allograft biopsy specimens, C4d stained endothelium of veins, arteries, and/or sinusoids in 2 (8%) of 25 cases of acute rejection with central vein involvement C4d staining was negative in biopsy specimens with no evidence of rejection. Results.-In small intestine, C4d labeled capillaries in 27% of cases with no evidence of rejection, 36% of cases with evidence of acute rejection, and 2 (28%) of 7 specimens of native normal small intestine. Objective.-To study immunohistochemical C4d staining as a potential diagnostic marker in liver and small intestine allograft biopsy specimens.Дesign.-Thirty-six small intestine and 71 liver specimens, including native specimens, allografts with and without histologic features of acute cellular rejection, and explants, were stained with antisera to C4d using an immunohistochemical method on formalin-fixed, paraffin-embedded tissue. C4d deposition in allograft biopsy specimens occurs at sites of antibody-mediated complement activation and has become one of the histopathologic criteria for diagnosis of humoral rejection in the kidney and the heart. Context.-Antibody-mediated humoral rejection in kidney and heart allografts is well recognized and is often associated with poor outcome.