Cognitive impairment is a core feature of schizophrenia. Previous studies have indicated that exposure to neurotropic infectious agents such as Herpes Simplex Virus type 1 may contribute to cognitive deficits and neuroanatomical abnormalities in individuals with schizophrenia. We examined the association between exposure to neurotropic infectious agents and cognitive function in 1308 participants in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. This sample included all of the individuals in the CATIE trial for whom baseline blood samples were available. Cognition was evaluated at baseline by a test battery which yielded composite scores in the domains of processing speed, verbal memory, vigilance, reasoning, and working memory as well as a summary neurocognitive score. Solid phase immunoassay techniques were used to measure IgG class antibodies to Herpes Simplex Virus type 1 (HSV-1), Herpes Simplex Virus type 2 (HSV-2), Cytomegalovirus (CMV), and to Toxoplasma gondii (T gondii) in the sera of the study individuals. We found a significant association between the neurocognitive summary score and antibodies to HSV-1 but not to HSV-2, CMV, or T. gondii. There was also a significant association between HSV-1 exposure and the Verbal Memory, Vigilance, and Processing Speed composite scores. HSV-1 may modulate the neurocognitive function of individuals with schizophrenia through its ability to establish latency in the central nervous system and undergo periodic reactivation. A better understanding of the role of HSV-1 may lead to better methods of treatment for the cognitive impairments associated with schizophrenia.