A number of studies have shown that substance dependence and creative performance are associated with changes in gray matter density (GMD). However, to date, only a few studies have investigated the changes in GMD in polydrug dependents. There has been also almost no empirical evidence for a link between creativity and drug dependence. In the present study, we compare polydrug dependents (maintenance treatment: n = 14, abstinent: n = 16) with a healthy control group (n = 17). Voxel-based morphometry was used to investigate GMD. Additionally, the groups were compared in terms of cognitive ability, creativity and personality. Compared with the control group, polydrug dependents showed a reduced GMD in superior fronto-media areas, including the cingulate gyrus bilaterally, the supplementary motor area bilaterally, the right frontal gyrus and the left anterior cingulate. These findings may be associated with decreased cognitive functions, which are associated with these frontal areas. Furthermore, compared with abstinent polydrug dependents, polydrug dependents in maintenance treatment showed a higher GMD in the left precuneus and in the left superior parietal lobe. Based on the assumption that these brain areas are associated with creativity, these results could indicate a higher creative ability in polydrug dependents in maintenance treatment. However, there were no group differences in creative performance. In addition, polydrug dependents also showed impairments in cognitive performance and personality. However, further research is needed to investigate the relationship between polydrug dependence and neuronal alterations of the brain.