Background: Gonadectomy is one of the most common procedures performed on dogs in the United States. Neutering has been shown to reduce the risk for some diseases although recent reports suggest increased prevalence for structural disorders and some neoplasias. The relation between neuter status and autoimmune diseases has not been explored. This study evaluated the prevalence and risk of atopic dermatitis (ATOP), autoimmune hemolytic anemia (AIHA), canine myasthenia gravis (CMG), colitis (COL), hypoadrenocorticism (ADD), hypothyroidism (HYPO), immune-mediated polyarthritis (IMPA), immune-mediated thrombocytopenia (ITP), inflammatory bowel disease (IBD), lupus erythematosus (LUP), and pemphigus complex (PEMC), for intact females, intact males, neutered females, and neutered males. Pyometra (PYO) was evaluated as a control condition. Results: Patient records (90,090) from the William R. Pritchard Veterinary Medical Teaching Hospital at the University of California, Davis from 1995 to 2010 were analyzed in order to determine the risk of immune-mediated disease relative to neuter status in dogs. Neutered dogs had a significantly greater risk of ATOP, AIHA, ADD, HYPO, ITP, and IBD than intact dogs with neutered females being at greater risk than neutered males for all but AIHA and ADD. Neutered females, but not males, had a significantly greater risk of LUP than intact females. Pyometra was a greater risk for intact females. Conclusions: The data underscore the importance of sex steroids on immune function emphasizing a role of these hormones on tissue self-recognition. Neutering is critically important for population control, reduction of reproductive disorders, and offers convenience for owners. Despite these advantages, the analyses of the present study suggest that neutering is associated with increased risk for certain autoimmune disorders and underscore the need for owners to consult with their veterinary practitioner prior to neutering to evaluate possible benefits and risks associated with such a procedure.