Dopaminergic and inflammatory systems have been proven to play an important role in the cognitive deficits of schizophrenia. Although increasing evidence indicates two systems have strong interaction, the relevant research on this interaction is still limited. Catechol-o-methyltransferase (COMT) and Interleukin-10 (IL-10) play critical functions in dopaminergic and inflammatory systems respectively, and their genetic polymorphisms are both associated with cognitive function. However, the interactive effect of their genetic polymorphisms has not been investigated. In this study, COMT Val158Met (rs4680) and IL-10 -592A/C (rs1800872) polymorphisms were measured in patients with chronic schizophrenia (n = 244) and healthy controls (n = 396), and their cognitive functions were assessed using the ?Repeatable Battery for the Assessment of Neuropsychological Status? (RBANS). We found that IL-10 alone had no effect on cognitive function, while COMT affected language ability and interacted with the schizophrenia (case vs control) or sex in multiple RBANS indexes. Additionally, we found there was a significant interactive effect between IL-10 and COMT polymorphisms on multiple cognitive indexes of RBANS. In detail, the analysis showed that the IL-10 polymorphism had opposite effects on cognitive function in different COMT genotype carriers; meanwhile, the polymorphism of COMT only had a significant effect on cognitive function in IL-10 C carriers. And this interaction was more significant in schizophrenia than in controls. Our study discovered for the first time, there is an interactive effect between IL-10 and COMT genetic polymorphisms on cognitive function, which is valuable for further investigations and drug administrations associated with both systems.