BACKGROUND We have demonstrated earlier that porcine corneal xenografts underwent an acute cell-mediated rejection in mice despite the absence of T cells. In the present study, we investigated the effect of complement depletion by cobra venom factor (CVF) on the corneal xenograft rejection in a pig-to-mouse model. METHODS Porcine corneas were orthotopically transplanted into C57BL/6 (B6) and severe combined immunodeficiency (SCID) mice. For complement depletion, 25 microg of CVF (1 g/kg bodyweight) was injected intraperitoneally on the day before and 1, 3, 5, and 7 days after transplantation. Graft survival was clinically assessed by slit lamp biomicroscopy and the median survival time (MST) was calculated. The grafts were histologically evaluated serially after transplantation using antibodies against CD4, CD8, NK1.1, and F4/80. RESULTS The CVF treatment significantly prolonged the porcine corneal xenograft survival in both B6 (MST 9.4 vs. 15.5 days; P = 0.0011) and SCID mice (MST 16.4 vs. 20.5 days; P = 0.0474). Histologically, whereas macrophages and CD4(+) T cells were progressively infiltrated into porcine corneal grafts in CVF-untreated B6 mice, the infiltration by both cells was markedly delayed and decreased in the xenografts in CVF-treated B6 mice. Likewise, macrophage infiltration, which was prominent in rejected porcine xenografts in SCID mice, was also reduced in CVF-treated SCID mice. CONCLUSIONS Our results suggest that complement depletion by CVF delayed, although did not prevent, an acute cell-mediated rejection in a pig-to-mouse corneal xenotransplantation.