Schizophrenia is known to impair reproductive and occupational functioning, and thus, the condition would appear to be a poorly adaptive trait. In contrast to expectations, the high frequency of schizophrenia, coupled with the existence of differing but analogous high schizophrenia risk polymorphisms across the globe, suggest that high risk schizophrenia genotypes could have experienced some positive rather than negative selection pressures. Indeed, the set of cellular and tissue processes influenced by schizophrenia – including manipulations of oligodendrocyte development, complement mediated immunity, VRK2, sulfation of heparin, IL-18, availability of glutamate, and interactions with sex hormones – overlaps with the set of cellular and tissue processes affected during Vaccinia encephalitis. Many schizophrenia-associated influences appear to oppose orthopoxvirus related influences; and many of the proteins suppressed in the schizophrenia phenotype are proteins either produced by or necessary for Vaccinia. Accounts from the early part of the 20th century affirm that Vaccinia encephalitis resembles Variola encephalitis; and genomic sequencing studies confirm significant homology between the species. On the basis of similarity of Variola to Vaccinia, and on the basis of evidence derived from studies on Vaccinia and other orthopoxviruses, it is proposed that high schizophrenia risk genotypes may have served a protective function against smallpox.