The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533) from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the at risk allele showed greater activations (P < 0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes may be in part due to this genetic variation.