To assess the value of DNA markers for the diagnosis of familial adenomatous polyposis (FAP) in South Africa, two highly informative CA-repeat polymorphisms (LNS CA-repeat in D5S346 and YN5.64c CA-repeat in D5S82) flanking the adenomatous polyposis coli (APC) gene, and three intragenic restriction fragment length polymorphisms (RFLPs) (exon 11/RsaI, exon 15.11/MspI, 3'UTR/SspI), were used for haplotype analysis in 13 South African families with the disease. The combination of these polymorphic markers proved to be highly informative and allowed an accurate diagnosis of FAP in 34/35 of the at-risk individuals analysed. Indirect molecular screening can therefore provide a comprehensive pre-clinical diagnostic test for FAP in South Africa. No predominant haplotype was found to be associated with FAP within the South African population. This suggests the absence of founder-type mutations in affected families and therefore marker studies remain important for the pre-clinical diagnosis of FAP in South Africa.