Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.