Mice immunized with acetylcholine receptor (AChR) purified from Torpedo californica form anti-AChR antibodies and often develop muscular weakness and flaccid paralysis closely resembling the human disease myasthenia gravis. This condition, termed experimental myasthenia gravis (EMG), is strain dependent in that the frequency of paralysis is much greater in some strains than in others. Differences in the frequency of EMG might result from differences in the immune system or the neuromuscular junction. In these studies, we have identified two loci, the major histocompatibility complex (H-2) region on chromosome 17 and the region that contains the structural genes for the constant region of immunoglobulin heavy chains (IgCH region) on chromosome 12, which significantly effect the probability with which a mouse immunized with T. californica AChR can be expected to become paralyzed. One genotype (H-2b, Ig-1b) correlated with high susceptibility to EMG in four strains with three dissimilar backgrounds. These studies demonstrate that susceptibility to EMG is a heritable trait determined by at least two distinct loci that are linked to regions of the mouse genome that regulate immune responsiveness.