We investigated the influence of gene mapping within the major histocompatibility complex on the susceptibility to Graves' eye disease. We studied 133 randomly selected patients with Graves' disease, many of whom had eye disease. HLA B8 and DR3 carried the greatest risk for disease but the difference between the two patient groups was not statistically significant. An earlier finding that Hungarian patients with a subset of B8, (B8 + DR7 +) had a greatly enhanced risk for eye disease was confirmed in Newfoundland patients. HLA B8 and DR7 are probably carried on different homologous chromosomes and their interaction enhances eye disease. HLA-DR4 was negatively correlated with eye disease. In particular, a subset of DR4 (B35 + DR4 +) appears to protect against eye disease. We have also derived the haplotypes of 22 probands, half of whom had eye disease. The haplotype data emphasized the high frequency of HLA A1 B8 DR3 C4A*QO and C4B*1 in both patient groups, 15% of the haplotypes in the group with eye disease and 25% in that without eye disease. Forty-one percent of haplotypes in the eye disease group and 32% in the no eye disease group were either C4A*QO or C4B*QO. In one proband with eye disease B8 and DR7 were carried on separate chromosomes. The phenotype DR4, C4A*3 C4B*1 was found in 3/20 haplotypes of patients without eye disease but in 0/20 of patients with eye disease. This finding is in keeping with the increased frequency of the DR4 C4A*3 C4B*1 in the patient group with no eye disease when 94 patients were phenotyped.(ABSTRACT TRUNCATED AT 250 WORDS)