Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease characterized by multiple gastrointestinal hamartomatous polyps and melanin spots on lips and buccal mucosa, with an increased risk for various cancers. The PJS gene, a potential tumour suppressor gene, encoding a serine/ threonie kinase (STK ll ), was mapped to chromosome 19pI3.3. To investigate the mutations of STK ll gene in Chinese with PJS, we analyzed its coding sequence in fifteen patients and twenty unaffected members of six families, including three multigenerational families with PJS and three sporadic families with PJS, by PCR, PCR-DHPLC and DNA sequencing techniques. Ten point mutations were found in the six families, including five missense mutations, one acceptor-splice site mutation, a nonsense mutation and three silent mutations. Our data showed that five missense mutations occurrd at codon 123 (CAG to CAT) in exon 2, codon 161 (ATT to AGT) in exon 4, codon 194 (GAC to GAG) in exon 4, codon 245 (CTC to TTC) in exon 5 and codon 354 (TTC to TTG) in exon 8. One kind of nonsense mutation was detected at codon 37 (CAG to TAG) in exon 1. Furthermore, we found an intronic mutation at a splice-acceptor site: a one base substitution from AG to AA in intron 4. These mutations were not detected in 20 normal DNA samples. In three sporadic families, only in one patient, we detected a missense mutation in exon 5. In addition, we found three silent mutations, which may cause polymorphisms of STK ll gene in introns 1(+36),3(-51) and 5(+27). These results indicated that the point mutation in STK ll might be involved in PJS pathogenesis. Mutation frequency is higher in the families suffering PJS in three or more generations than that of the sporadic cases.