Herpes simplex virus 1 (HSV-1) tends to replicate in the temporal cortex and can damage the limbic system. The presence of serum antibodies to HSV-1 is associated with cognitive impairment in adults with schizophrenia, suggesting that cerebral gray matter abnormalities might distinguish patient subgroups defined by HSV-1 exposure. We assessed 43 adult outpatients with schizophrenia. The assessment included clinical interviews, neurocognitive testing, anatomic brain magnetic resonance imaging and measures of serum IgG antibodies specific to herpes simplex viruses 1 and 2. We then compared 25 patients who tested positive for antibodies to HSV-1 with 15 who were seronegative for both HSV-1 and HSV-2. The seropositive patients performed significantly worse than the seronegative patients on four neuropsychological measures of psychomotor speed, executive functioning, and explicit verbal memory. Voxel-based morphometric analyses revealed that the same patients showed reduced gray matter volume in the anterior cingulate and areas of the cerebellum. Finally, performance on the test of psychomotor speed and executive functioning that showed the largest between- group effect size correlated with reduced gray matter volume in some of the same brain regions (cingulate and cerebellum) that distinguished the two HSV-1 subgroups. In these outpatients with schizophrenia, HSV-1 seropositivity and performance on a cognitive test that is highly sensitive to it co-localize to closely overlapping brain regions.