Human leukocyte antigen (HLA) tissue-typing studies on patients with genetically transmitted hypertrophic cardiomyopathy have demonstrated an HLA linkage in a Caucasian and black patient group and an HLA-DR locus association in a Japanese population sample. To confirm whether a specific HLA antigen(s) might serve as a marker for hypertrophic cardiomyopathy, we performed tissue-typing studies on 50 unrelated, normotensive North American Caucasians with the disorder. Patients were subdivided into three hemodynamic subgroups: obstructive (35), provocable (ten), and nonobstructive (five). Although there was an increased frequency of the B12 and AW32 HLA antigens in the total group, after correction of P values for the number of antigens studied, the associations were not statistically significant. Analysis of the HLA antigen frequencies in the three hemodynamic subgroups yielded no statistically significant HLA-A, B, or C locus associations, and no unusual deviation in linkage disequilibrium between A and B locus antigens was observed. We conclude that although on the sixth chromosome there may be a susceptibility gene for hypertrophic cardiomyopathy, which segregates with a specific haplotype in a given family, no specific HLA-A, B, or C locus antigen was found useful as a marker. HLA-DR locus antigen typing might prove useful in this population.