This study examines HLA and ABO gene polymorphisms in 8 major ethnic regions in Indonesia ie Sumatra, Java, Kalimantan, Bali, Sulawesi, Lesser Sundas, Moluccas and Irian. Blood samples comprising 12 ethno-linguistic groups were collected from 863 healthy unrelated subjects. Red cells and plasma were used for forward and reverse ABO blood group serological typing. Genomic-DNA was extracted from the buffy coat, and the HLA class II genes ie DRB1, DRB3, DRB5 and DQB1 were studied using PCR-SSO, PCR-RFLP and reverse hybridisation PCR-SSO. Thirty two DRB1, 5 DRB3, 6 DRB5 and 16 DQB1 alleles, and 10 DRB1-DRB5, 23 DRB1-DRB3 and 26 DRB1-DQB1 putative haplotypes with significant linkage disequilibrium were identified. Three new DRB alleles with distinctive restriction enzyme patterns to any previously described HLA class II alleles, were detected and confirmed by direct DNA sequencing analysis. These alleles have been named by the WHO Nomenclature Committee for Factors of the HLA System as HLA DRB1*1431, HLA-DRB1*0819 and HLA-DRB3*0303. Two unusual haplotypes were seen ie DRB1*0303-DQB1*02 in the Dayaks and DRB1*12021-DQB1*0502/0503 in the Timorese. DR allele frequencies were dominated by increasing incidence of DR15 from west to east (29.7% to 58%), followed by a decreasing frequency of DR12 and an increase of DR11. Overall ABO blood group frequencies were O(43.5%), B(25.8%), A(23.1%) and AB(7.4%). Eastward ABO trends consisted of an increasing O and decreasing B & AB blood group frequencies. Significant DR, DRB1, DQB1 and ABO differences revealed 10 genetically defined ethnic groups ie the Bataks, Minangs & Palembangs, Javanese, Dayaks, Balinese, Minahasans, Makasarese, Timorese, Moluccans and Irianese. It is suggested that the DR15(DRB1*1502) and DR11(DRB1*1101) alleles and the O blood group gene were originally linked to, or much higher in frequency in, the early settlers of Indonesia ie the Melanesoids, Australoids and Negritos; and that the DR12(DRB1*12021) allele and the B blood group gene were originally linked to, or much higher in frequency in, the later settlers ie the Austronesians known as the Proto- and Deutero-Malays. While DRB1*1502 and DRB1*1101 alleles showed an association with susceptibility to malaria, the DRB1*12021 and DRB3*0301 alleles were associated with resistance to malaria.