DNA sequencing of HLA class II alleles has revealed a degree of polymorphism much greater than was expected on the basis of the standard serological typing methods. Amplification of the polymorphic second exon of the class II genes using the polymerase chain reaction, followed by hybridization with sequence-specific oligonucleotide probes, allows the unambiguous identification of alleles which could not be detected previously. Using the protocols of the Eleventh International Histocompatibility Workshop, we have applied this procedure for the typing of several individuals and their families with suspected alleles that had been observed using serology, cellular typing and restriction fragment length polymorphism (RFLPs). These included an allele related to DRw8 and DRw14, which has only been observed in the mixed ancestral South African population. In addition, unusual combinations of class II genes forming unique haplotypic associations were seen.