T o investigate the specific contribution of select MHC class II genes on the development of murine lupus, H-2 congenic (NZB x BXSB)F1 hybrid mice bearing either H-2b/b, H-2d/b, or H-2d/d haplotypes were generated. We compared the clinical development (autoantibody production and glomerulonephritis) of systemic lupus erythematosus (SLE) in these three F1 hybrids in the presence or absence of the mutant gene, Yaa (Y chromosome-linked autoimmune acceleration), which normally accelerates the progression of murine SLE. (NZB x BXSB)F1 hybrid female mice bearing either the H-2b/b or H-2d/b haplotype developed a rapid course of severe SLE, while the appearance of disease was markedly delayed in H-2d/d hybrid females. However, in the presence of the Yaa gene, H-2d/d F1 males developed SLE as severe as H-2b/b and H-2d/b F1 males. These data indicate that (a) the conventional H-2b is a haplotype leading to susceptibility for murine SLE, while H-2d is a relatively resistant haplotype; (b) the H-2b haplotype exhibits a dominant effect on autoimmune responses, similar to the classical MHC-linked Ir gene effect; and (c) most strikingly, the Yaa gene totally abrogates the MHC effect on murine lupus in (NZB x BXSB)F1 hybrid mice.