Recently, we and others have shown the prolongation of xenograft survival with the use of transgenic pigs bearing human CD 59 and DAF complement regulatory proteins (CRP). We now report heart transplantation using a new line of transgenic pigs bearing a different human CRP, membrane cofactor protein (MCP, CD 46). We transplanted three MCP transgenic and three wild-type porcine hearts into baboons suppressed with cyclosporine, methylprednisone, and rapamycin or cyclophosphamide. In addition, recipients were treated with extracorporeal plasma perfusion to remove alpha-Gal reactivity. The wild-type grafts were rapidly rejected at 60 to 80 min. Two functioning MCP hearts were removed after 5 and 46 h for histological examination. One MCP heart showed vigorous function until postoperative day 16. Immunohistochemistry of both wild-type and MCP-transgenic hearts showed strong deposition of IgM. In contrast, there was less MAC deposition in the transgenic graft as compared to the wild-type control. MCP is another CRP capable of decreasing the features of hyperacute rejection of cardiac xenografts in baboon recipients.