<p>The major histocompatibility complex (MHC) plays a central role in immune responses, with strong links to both infectious disease resistance and autoimmune conditions. In typical mammals, such as humans, the MHC is large and complex, comprising many genes and exhibiting weak associations with infectious diseases, but strong associations with autoimmunity. In contrast, the chicken MHC is small and simple, with only one dominantly-expressed class I and class II gene, and strong associations with resistance to infectious pathogens; however, its role in autoimmunity is less well understood. This raises a question: Does the simplicity of the chicken MHC reduce the risk of autoimmunity? In this speculative review, we explore the question by comparing chickens and typical mammals, and by considering the spectrum of MHC alleles from promiscuous generalists to fastidious specialists. We suggest that comparing the spectrum of alleles within a single species, such as chickens, may offer a way to test the link between MHC complexity and autoimmunity. Although much work remains, this approach could provide new insights into the balance between immune protection and self-tolerance.</p>