A better understanding of the factors associated with psychotic symptoms could aid early identification and treatment of psychotic disorders. Previous studies have typically utilized cross-sectional study designs and have focused on individuals with psychotic disorders. Thus, examination of promising correlates of psychotic symptoms using longitudinal designs among more broadly defined populations is warranted. Two such correlates are neuregulin-1 (NRG1) genotypic variation and depression symptom severity. Both NRG1 and depression symptom severity have cross-sectional evidence for an association with psychosis but their affect on longitudinal patterns of psychotic symptoms and their potential interaction effects are less clear. Using repeated measures analysis of variance and covariance we modeled the main and interaction effects of NRG1 genotypic variation and depressive symptom severity on longitudinal psychotic symptom patterns in 301 primary care attendees assessed annually over 4 years. One-fifth (19.9%) of the participants reported one or more psychotic symptoms over the 4-year assessment period. We observed a curvilinear (i.e., cubic) association between depression symptom severity at baseline and longitudinal patterns of psychotic symptoms but did not observe a main effect for NRG1 genotypic variation on psychotic symptom patterns. However, NRG1 rs6994992 genotype moderated the curvilinear association between depression symptom severity and psychotic symptom patterns. Specifically, depression symptom severity had less of an effect on longitudinal psychotic symptoms among carriers of the rs6994992 TT genotype compared to CC and CT carriers. Our findings suggest a curvilinear association between depression symptom severity and longitudinal patterns of psychotic symptoms that is moderated by NRG1 genotype. © 2013 Wiley Periodicals, Inc.