The polygenic predisposition to RA is conferred particularly by disease susceptibility sequences in the HVR3 of HLA DRB1 present in those subtypes of DR4 and DR1 that are associated with RA. The aim of this study was to examine predisposing interactions between genes encoding HLA and immunoglobulin molecules. Accordingly, we compared the genetic background of 114 Australian patients with RA with that of Australian controls of similar ethnic background. We identified HLA-A, B, and DR phenotypes serologically, HLA-DR, DQ alleles, and subtypes of DR4 by DNA typing, and Gm allogenotypes and immunoglobulin switch region polymorphisms by RFLP. For the subjects with RA, we confirmed previously reported observations that included an excess of females, 71%, a high frequency of HLA types DR4 or DR1 of 77% versus controls 47%, and a high frequency of the HVR3 susceptibility sequences of 76%, with 24% homozygous, and 52% heterozygous for the sequences. We observed other genetic correlations in RA that included increases in frequencies of DR4 in males, DR1 in females, the class I specificity HLA-B27 overall but more particularly in females, 24% in females, versus 5% of controls, HLA- DQB1*0302 (DQ8) in DR4*0401-positive patients, and the Gm allogenotype 1,2,3;23±;5,10, 15% of patients versus 4% of controls. Examination of switch region genes gave no evidence of differences in the polymorphisms distributions. Thus, the major genetic risks for RA that are conferred by female gender and the HVR3 of HLA DRB1 are modulated by interactions between gender and HLA class I and class II alleles, and the Gm allogenotype.