Background The aim of this study is to characterise the effects of already identified genetic risk variants on social cognitive deficits in schizophrenia. Although the aetiology of schizophrenia is largely unknown, it is increasingly clear that genetic and environmental interactions contribute to cognitive deficits associated with this disorder. The ‘Immune Hypothesis’ suggests that schizophrenia is often predicted by early environmentally-driven immune challenges, and genetically driven sub-optimal immune responsiveness. In the largest genetic study of schizophrenia to date, recent Genome-Wide Association Studies (GWAS) have established the strongest association with schizophrenia was found at a region of the genome that is synonymous with immune function- the major histocompatibility complex, or MHC. Social cognitive deficits are core features of Schizophrenia, which relate to genetic risk. The current study analyses the effects of immune challenge (genetic and environmental) on social cognition, examining a set of genes related to immune function and schizophrenia risk, as well as environmental factors that may contribute to cognitive deficit. Methods To test if genetic variants related to immune function impair cognition, genes were selected by cross referencing “Immunology” Gene Ontology lists with the most recent list of genes implicated in GWAS for schizophrenia. 1013 participants were genotyped and cognitively assessed in an Irish population of schizophrenia sufferers and healthy controls, and this cohort was used for primary analysis of a gene-cognition relationship. A separate cohort of already collected data was also examined from the Avon Longitudinal Study of Parents and Children (ALSPAC) for replication of results and mediation analysis, consisting of ~5000 participants. Block regression analysis using SPSS statistical software was performed, testing a relationship between genetic risk levels and cognitive deficits. In a second element to the study, environmental factors were examined as possible mediators of the relationship between genetic risk variants and cognitive impairment (PROCESS mediation, SPSS) in the ALSPAC sample. Results Regression analysis suggests that 7 of genetic variants selected contribute to impairments in cognition across an Irish sample, and these findings were replicated in the ALSPAC sample. Cognitive deficits overlapped for the majority of genes examined, across domains of social cognition, IQ and episodic memory. In examining ALSPAC as a replication sample, many of the same genetic variants also showed negative effects on social cognition, as well as more generalized effects of these genes on various cognitive domains. In mediation analysis, environmental factors such as childhood abuse were also found to impact on this gene-cognition relationship. Discussion The Immune 8 may serve as significant risk markers for schizophrenia, and further elucidate aetiology of this disorder. Future studies on neurobiology of social cognition, and greater knowledge of genetic risk may establish targets for interventions. Childhood abuse was also found to be significantly related to cognitive deficit. The role of environmental stressors contributing to genetic risk and immune function is an interesting avenue for future research in schizophrenia.