Objective Intellectual decline is common in schizophrenia and predicts functional outcome. While many patients undergo intellectual decline that typically predates the onset of symptoms, few studies have investigated the underlying mechanism through which this occurs. The current study assessed the relationship between intellectual decline in schizophrenia and genetic variation in dysbindin-1 (DTNBP1). Methods We assessed cognitive decline in 183 Caucasian patients with schizophrenia using a proxy measure of premorbid IQ with which current general cognitive ability (g) was compared. We then tested for a relationship between the risk haplotype identified in previous work (CTCTAC) and intellectual decline. Results We found that carriers of the CTCTAC haplotype, demonstrated a significantly greater decline in IQ as compared with non-carriers (p =0.05). Conclusions These data suggest that DTNBP1 influences the severity of intellectual decline in schizophrenia and may represent one underlying cause for heterogeneity in cognitive course.