Progressive familial intrahepatic cholestasis (PFIC) is caused by mutations of the bile salt export pump or the multidrug resistance P-glycoprotein, resulting in chronic hepatic failure. Partial external diversion of bile or ileal bypass is effective in some cases and, in others, liver transplantation (OLT) is necessary. Forty-two children were included in this study. Twenty-six children suffered from PFIC type 2 and 16 from PFIC type 3. Symptoms included pruritus, cholestasis, liver cirrhosis, and growth retardation. Seventeen patients received external biliary diversion. Ten had to undergo OLT in the following course. As of this report, three of the remaining patients were on the wait list for OLT. Twenty-three children received a liver graft primarily with excellent outcome. Our data show that OLT is the option of choice in symptomatic PFIC and whenever liver cirrhosis is present. We suggest a very restrictive recommendation of external biliary diversion. However, gene therapy may be a future option for children with PFIC.