Catechol-O-methyltransferase (COMT) gene variants have been reported to be implicated in the pathogenesis of psychotic symptoms in schizophrenia, especially in negative symptoms. These symptoms including apathy, blunted affect, social withdrawal and motor retardation. Neuroimaging studies suggested that negative symptoms appear to be associated with impaired activities of the prefrontal cortex in particular the dorsolateral prefrontal cortex (DLPFC). Given that the COMT gene is highly expressed in the DLPFC, it is poorly understood whether the disease state and COMT val158met polymorphisms have main and interactive effect on the resting state functional connectivity (RSFC) of DLPFC-related pathways. To this end, fifty-five first episode schizophrenia (FES) and fifty-three healthy controls were genotyped using blood samples and underwent magnetic resonance imaging scanning. Seed-based voxel wise functional connectivity analysis was performed by placing bilateral pairs of seeds with DLPFC in area 46 defined by Brodmann's atlas. A two-ways ANCOVA model was performed with val158met genotypes and disease state as the between subjects factors. Significant disease × COMT interactive effect was found mainly in the left DLPFC with the left anterior cingulate cortex, right precuneus, right superior parietal gyrus, which were overlapped with disease main effect. And these RSFC had positive correlations with affective blunting scores in FES patients with val homozygotes, but not with met carriers. Our results showed that the disease and the genotypes in COMT gene have significant interactive effect on RSFC of DLPFC and provided evidence for a disease-dependent pattern of gene action.