Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies, accompanied by olfactory regional alterations in neuroimaging. Some evidence suggests that olfactory gene receptors have additional functions in the brain, related to their direct anatomical connection to the limbic system. For example, odor sensing may explain HLA-dissimilar mate selection in humans and animals. Recently, a large cluster of the olfactory receptor (OR) genes was mapped in proximity to the HLA locus on chromosome 6. The HLA and linked OR genes are clustered in haplotypes and are highly polymorphic. This finding may constitute an association among autoimmunity, psychiatric disorders and smell impairment. In this review, we examine the anatomic, genetic and clinical clues that may support an association among these conditions.