It is widely known that there is a high prevalence of cigarette smoking in schizophrenia. One of the explanations is the self-medication hypothesis. Based on this hypothesis, it has been suggested that nicotine has procognitive effect or even neuroprotective effect in schizophrenia. However, cigarettes contain numerous neurotoxic substances, making the net effect of cigarette smoking on brain function and structure complex. Indeed, recent studies have called into question the self-medication hypothesis. We aimed to test whether there is an interaction between diagnosis and smoking status in gray matter volume, ie, whether smoking has specific effects on gray matter or whether main effects of these 2 variables additively affect common brain regions. Magnetic resonance imaging (MRI) images were obtained from 4 groups: (1) normal controls with no smoking history, (2) normal controls currently smoking and/or with a past history of smoking, (3) schizophrenia patients with no smoking history, and (4) schizophrenia patients currently smoking and/or with a past history of smoking. We used voxel-based morphometry to compare gray matter volumes among the 4 groups. We did not find any interaction between diagnosis and smoking, but we did find negative additive effects of schizophrenia diagnosis and smoking status in the left prefrontal cortex. The decrease in left prefrontal volume was associated with greater numbers of cigarette pack years and severe positive and negative symptoms. The current findings do not support the neuroprotective effect of smoking on gross brain structure in schizophrenia, emphasizing the necessity of longitudinal studies to test causal relationships among these variables.