Human infections with the tissue nematode Onchocerca volvulus result in a variety of clinical conditions that possibly include protective immunity. In a West African area hyperendemic for human onchocerciasis, 120 residents were classified according to clinical and laboratory findings as presenting with generalized onchocerciasis, localized onchocerciasis, or as being putatively immune. The three groups differed in the distribution of HLA-D variants as determined by DNA typing. The most pronounced differences were found among alleles of the DQ loci. The haplotype DQA1*0501-DQB1*0301 was significantly more frequent among putatively immune individuals than among patients with generalized or localized disease. Conversely, DQA1*0101-DQB1*0501 and, independently, the allele DQB1*0201 were more frequent in generalized disease than in localized disease or putative immunity. In these correlations, the frequencies of allelic variants were in localized disease intermediate to those of the two other groups. The only distinct association found with localized disease was that of the DP allele DPB1*0402. The findings indicate that HLA-D variants influence the course of O. volvulus infection and help to define a state that may reflect protective immunity.