Introduction: Progressive familial intrahepatic cholestasis (PFIC) type 1 and type 2, characterized by normal serum gamma-glutamyltransferase levels, are caused by defects in FIC1 and BSEP, respectively. Previous reports showed that PFIC type 1 patients had bland intracanalicular cholestasis, whereas non-type 1 patients were marked by non-specific giant cell hepatitis with moderately to markedly elevated serum transaminase levels. However, there has been only one study comparing the clinical features of these two genotypes on the basis of a molecular diagnosis. To investigate the occurrence of genetic mutations and clinical differences between the two genotypes, we performed mutational analysis in FIC1 and BSEP genes in patients with PFIC phenotypes and normal gamma-glutamyltransferase activities. Methods: The coding region and exonintron boundaries of the FIC1 and BSEP gene were sequenced in 17 unrelated Japanese PFIC patients with normal serum gamma-glutamyltransferase activities. All patients were Japanese, from various parts of the country. The following clinical data were collected: age at onset, clinical signs of cholestasis, serum alanine aminotransferase (ALT) levels, liver histology, growth, and therapy including liver transplantation. Results: All patients had novel disease-causing mutations in FIC1 or BSEP. Of the 17 patients, 13 carried FIC1 mutations (5 homozygotes, 7 compound heterozygotes, 1 heterozygote), and 4 carried BSEP mutations (1 homozygote, 2 compound heterozygotes, 1 heterozygote). FIC1 mutations included 8 missense mutations, 2 nonsense mutations, 2 insertions, 1 deletion and 3 splicing mutations. BSEP mutations consisted of 5 missense mutations and 1 exon skipping. There were overlap in ALT levels between PFIC type 1 and PFIC type 2 patients, and other clinicopathological features were insufficient to differentiate between the two genotypes. However, complications such as intractable diarrhea or severe liver steatosis occurred after transplantation in 12 of the 13 patients with type 1, while they never occurred in the type 2 patients. Conclusion: PFIC type 1 is the major type in Japan, and frequently causes severe complications such as intractable diarrhea and liver steatosis after liver transplantation. For predicting these unfavorable complications, genetic diagnosis is needed for case of PFIC before liver transplantation, because it is impossible to distinguish between PFIC type 1 and PFIC type 2 by clinical findings exclusively.