Numerous studies have shown that proinflammatory cytokines produced by immune cells in the brain have deleterious effects on cognitive functions. In contrast, IL-10, an anti-inflammatory cytokine, can be neuroprotective and prevent neuronal dysfunction. However, few studies have linked the role of IL-10 to cognitive deficits in schizophrenia. In this study, serum IL-10 levels and genotypes for the IL10 -592 A/C promoter polymorphism were measured in a cohort of first-episode drug-naïve schizophrenic patients (FEDN-S) (n = 256) and healthy control subjects (HC) (n = 540). All participants were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). In a separate transcriptomic data set containing 577 healthy human brain samples, we analyzed IL-10 and IL-10 RA/B-associated genetic networks in order to ascertain potential functions for IL-10 in the brain. We found a significant difference in allelic frequency between FEDN-S and HC subjects. The A allelic variant was associated with reduced serum IL-10 levels and worse attentional performance in FEDN-S but not in HC subjects. Moreover, serum IL-10 levels were correlated with the extent of cognitive impairment, especially attentional performance in the schizophrenic A-allele carriers. In human brain transcriptomic coexpression analysis, we found that genes most significantly co-expressed with IL10 were associated with synaptic vesicle transportation, and both IL10RA and IL10RB were most significantly co-expressed not only with genes that regulate inflammation but also with those that participate in synaptic formation. The IL10-592 A/C genetic variant was more common in schizophrenic patients than HC and was associated with lower IL-10 serum levels and worse attentional performance in these patients. Furthermore, the IL10 gene and its receptors in the healthy human brain appear to regulate inflammation and synaptic functions that are important for cognition, and hence its deficiency in schizophrenia may contribute to cognitive impairment.