Individuals with an at risk mental state (ARMS) are at greatly increased risk of developing a psychotic illness. Risk of transition to psychosis is associated with regionally reduced cortical gray matter volume. There has been considerable interest in the interaction between psychosis risk and substance use. In this study we investigate the relationship between alcohol, cannabis and nicotine use with gray matter volume in ARMS subjects and healthy volunteers. Twenty seven ARMS subjects and 27 healthy volunteers took part in the study. All subjects underwent volumetric MRI imaging. The relationship between regional gray matter volume and cannabis use, smoking, and alcohol use in controls and ARMS subjects was analysed using voxel-based morphometry. In any region where a significant relationship with drug was present, data were analysed to determine if there was any group difference in this relationship. Alcohol intake was inversely correlated with gray matter volume in cerebellum, cannabis intake was use was inversely correlated with gray matter volume in prefrontal cortex and tobacco intake was inversely correlated with gray matter volume in left temporal cortex. There were no significant interactions by group in any region. There is no evidence to support the hypothesis of increased susceptibility to harmful effects of drugs and alcohol on regional gray matter in ARMS subjects. However, alcohol, tobacco and cannabis at low to moderate intake may be associated with lower gray matter in both ARMS subjects and healthy volunteers-possibly representing low-level cortical damage or change in neural plasticity.