Few data exist on associations of class II and class III alleles of the major histocompatibility complex (MHC) and susceptibility to systemic lupus erythematosus (SLE) in Mexican Americans, a group of predominantly mixed Spanish and Native American ancestry. Therefore, MHC class II alleles (HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 alleles) and C4 allotypes were determined in 52 Mexican American SLE patients and 105 ethnic-matched controls. HLA-DRB1*0301 and C4A*Q0 were each increased in the SLE patients, especially HLA-DRB1*0301 in those with anti-Ro/SSA autoantibodies. C4A*Q0 was associated with HLA-DRB1*0301 only in a minority of patients and controls. Anti-U1RNP antibodies were significantly associated with the presence of HLA-DQB1*0302, and the risk for the production of anti-Ro antibodies was heightened by the presence of at least three (out of four possible) DQA1 chains possessing a glutamine at position 34 and/or DQB1 chains a leucine at position 26 of their outermost domains. Thus the HLA class II and C4 null allele associations that have been noted in other ethnic groups are also found in Mexican Americans, suggesting shared susceptibility factors across ethnic lines in predisposition to SLE.