Hereditary complete C4 deficiency (C4def) is a very rare condition that predisposes to immune complex disease and end-stage renal failure. Whether such patients should undergo renal transplantation is debated. The clinical outcome of five transplantations in three C4def patients is described. The first patient lost one allograft after 6 years because of chronic allograft rejection. Back on dialysis, he suffered from meningitis caused by Neisseria menigitidis and Aspergillus. One year after a second transplantation under alemtuzumab induction, he developed fulminant Kaposi's sarcoma and died. His sister is now 6 years post-transplantation without complications. The third patient lost his first graft after 3 years because of chronic allograft nephropathy and recurrence of glomerulonephritis. He has now been living with a second graft for over 9 years. He suffered from pneumonia, a generalized varicella infection and Hemophilis parainfluenzae bronchitis. Patients with complete C4def are at increased risk for infection after kidney transplantation. Under certain precautions and with judicious use of immunosuppression, good long-term results are achievable.