We have investigated the HLA-DRB and -DQB gene polymorphism in 131 myasthenia gravis (MG) patients. The HLA genotypes in these patients were assigned by means of restriction fragment length polymorphism (RFLP)-defined DR-DQ haplotypes, correlating to serologic HLA class II typing. Using this technique we could, among randomly selected non-thymomatous (NT)-MG patients, confirm the strong association to DR3, and 70% of the patients were found to carry a specific DR3-positive DR-DQ haplotype, T-3.1. Furthermore, an analysis of T-3.1- NT-MG patients revealed that 59% were T-4.1+ (DR4, DQw8). Thymic hyperplasia was found in approximately 85% of the T-3.1+, as well as of the T-4.1+/3.1- patients. As previously observed, we found a clear dominance of females among the T-3.1+ NT-MG patients. However, among T-4.1+/3.1- patients, males were as common as females. Furthermore, the T-4.1+ patients were significantly older at the onset of disease than those who were T-3.1+. In female MG patients, the DRw15-Dw2-positive haplotype T-2.1 was strongly correlated with the presence of thymoma (T-MG). These data indicate that the HLA associations in early vs late onset of NT-MG are different, and that female patients with and without thymoma differ from each other with regard to HLA markers. Thus, at least three different HLA DR-DQ associations are found in subgroups of idiopathic MG.