Associations of human leukocyte antigen DR2 (HLA-DR2) and HLA-B7 with presumed ocular histoplasmosis syndrome (POHS) in the United States has been previously described. However, these associations were determined by means of low-resolution, complement-dependent cytotoxicity assays for HLA-A, HLA-B, and HLA-DR molecules. To determine whether POHS is associated with other HLA alleles within the HLA-A, HLA-B, HLA-DR, and HLA-DQ loci, we performed a case control study of 34 patients diagnosed with macular choroidal neovascular membrane secondary to POHS and 45 healthy control individuals. Peripheral blood-derived DNA from the study patients was typed for HLA genes by means of sequence-specific primers that gave low-medium allele resolution. Significant associations were observed between HLA-B7 (X2 = 14.30, pc = 0.004, relative risk = 8.23), HLA-DR15 (X2 = 29.08, pc = 0.000001, relative risk = 27.50), and HLA-DQ6 (X2 = 23.09, pc = 0.00001, relative risk = 27.43) and POHS. Because there are strong linkage disequilibria between HLA-DR15 (a subtype of HLA-DR2) and HLA-B7 as well as HLA-DQ6, the significantly higher association of HLA-DR15 and HLA-DQ6 with POHS as compared to HLA-B7 suggests that the former alleles mediate susceptibility to the disease. In conclusion, there is a significant association between the HLA-DR15/HLA-DQ6 haplotype and development of choroidal neovascular lesions in POHS.