Tropical splenomegaly syndrome (TSS) develops as a result of an atypical immune response to recurrent malarial infection. In general a low prevalence disorder, in the Upper Watut Valley of New Guinea TSS affects more than 80% of the inhabitants. We have studied the association of antigens and haplotypes of HLA-A,B,C, DR, and DQ loci with the severity of TSS as judged by the degree of splenomegaly in 77 unrelated Watut. The study confirmed the previously observed lack of association of TSS with HLA-A and B locus antigens. By contrast, HLA-DR2 was found to be more frequent in patients with gross splenomegaly than in those with moderate splenic enlargement. No two-locus haplotypes were, however, found to be significantly associated with TSS.