Background While research has examined brain structure in individuals who use alcohol or nicotine, heavy drinking smokers comprise a unique subpopulation of substance users for whom less is known about the relationship between alcohol or nicotine use and structural brain abnormalities. Objectives The present study examined gray matter morphometry in a sample of 39 heavy drinking smokers (24 males, 15 females) in relation to alcohol and nicotine dependence and quantity of use. Methods Traditional voxel-based morphometry techniques were employed for preprocessing of imaging data. One multiple regression analysis for alcohol and nicotine dependence severity and another for alcohol and nicotine quantity of use were conducted, while controlling for age, gender, and total intracranial volume (ICV). Results Alcohol dependence severity was significantly negatively associated with gray matter density in the hypothalamus (p < 0.001, uncorrected) and the right superior frontal gyrus (p < 0.001, uncorrected), while controlling for nicotine dependence severity, age, gender and ICV. There were no significant relationships observed with respect to nicotine dependence severity, quantity of alcohol use, or quantity of nicotine use variables and gray matter density. Conclusions These findings suggest that within heavy drinking smokers, alcohol dependence severity is significantly related to alterations in brain structure, while this effect is not seen for quantity of alcohol or nicotine use, or severity of nicotine dependence. The current findings help clarify the contribution of alcohol and nicotine effects on brain structure, which could aid in understanding their neurocognitive consequences in heavy drinking smokers.