Introduction: Cognitive deficits and metabolic disturbances are among the main determinants of functional impairment and reduced life expectancy in patients with schizophrenia, and they may share underlying biological mechanisms. Among these, interleukin-1β (IL-1β), a key mediator of inflammatory response, is of particular interest. IL-1β C-511T polymorphism has been associated with neuropsychiatric conditions and, in the general population, with cognitive and metabolic alterations. This study aims to evaluate the effects of the IL-1β C-511T polymorphism on both cognition and metabolic syndrome in a sample of patients affected by schizophrenia, with a focus on sex differences. Methods: 138 patients with schizophrenia were assessed for metabolic parameters and neurocognitive measures by means of the Brief Assessment of Cognition Scale. The effects of IL-1β C-511T polymorphism on cognition and metabolic syndrome were evaluated in the context of general linear models. Results: The analysis showed a significant interaction between IL-1β genotype and sex on 2 core cognitive domains. In detail, among CC homozygous, females outperformed males on processing speed, while among T carriers, males outperformed females on executive functions. A significant interaction also emerged between metabolic syndrome, sex, and IL-1β genotype for executive functions, with worse performance for T carrier females with metabolic syndrome. No significant direct effect was observed for metabolic syndrome on cognition. Conclusion: These findings support the hypothesis that IL-1β polymorphism could play a key role in mediating the complex and refined relationship between metabolic syndrome and cognitive performance.