Using national administrative data from the Department of Veterans Affairs (VA), clinical change in veterans with schizophrenia and comorbid substance abuse and dependence (n = 249) was assessed with the Addiction Severity Index. Outcomes among those switched or maintained on an atypical antipsychotic were compared with those treated with conventionals. For the entire sample and those on an atypical during the last assessment, paired t-tests showed significant decreases in the alcohol and psychological ASI scores. However, multivariate analysis showed no greater improvement in alcohol, drug, or psychological scores in individuals who were switched to (n = 33) or maintained on (n = 161) an atypical antipsychotic as compared to those who were treated with conventional at the final assessment (n = 55). Patients treated with atypical antipsychotics achieved no greater improvement in substance-related outcomes that patients who were not.