OBJECTIVE: This research was conducted to determine if history of substance abuse confers poor prognosis in schizophrenia as measured by onset of illness and treatment outcome. METHODS: This was a post hoc, pooled analysis of four randomized, double-blind, 24-28 week studies of schizophrenia treatment. All treatment groups were collapsed for a total of 1627 patients and 142 patients with a history of substance abuse at any time. Positive and Negative Syndrome (PANSS) scores and onset of illness were compared between patients who had history of substance abuse (males, n=116; females, n=26) and patients who did not have history of substance abuse (males, n=932; females, n=533) using analysis of variance. RESULTS: Patients with a history of substance abuse had an earlier onset of illness in both male and female patients. History of substance abuse also had a negative effect on treatment outcomes. Specifically, patients with a history of substance abuse had less improvement in PANSS total and subscores than other patients. The differences in PANSS total (p<0.01), PANSS positive (p=0.02), PANSS negative (p=0.03), and PANSS general psychopathology (p=0.02) scores were statistically significant for male patients with history of substance abuse. CONCLUSIONS: History of substance abuse is an important factor to consider when treating patients with schizophrenia, as these patients have an earlier onset of schizophrenia and poor response to treatment compared to other patients. Further studies are needed to determine if substance abuse promotes schizophrenia onset; or alternatively, certain traits predispose individuals to both substance abuse and schizophrenia.