ABSTRACT Background This prospective study aims to report on the prevalence of depression and anxiety levels, in a sample of Greek prisoners with a history of substance and alcohol use. Methods The study comprises 100 male prisoners with a history of substance and/or alcohol use, in the Grevena Correctional Facility, in Northern Greece. BDI AUDIT, DUDIT, CAGE, STAI Y-1 & Y-2 and SCL-90 R were used. Results Sixty-three percent of study participants stated they had mental health problems. Another 37% stated they were on antidepressants, 16% on anti-anxiety medication, and 7% on antipsychotic medication, while only 34% were not on medication. Linear regression was utilized to identify independent predictors for each of the questionnaires scores, adjusting for age. Conclusion The prevalence of depression among Greek prisoners with history of substance and alcohol use is much higher than in the general population in Greece and even between other inmate groups. Also anxiety levels of these prisoners were significantly elevated. This is the latest study in Greek prisons and the only one concerning inmates with history of dependence. Therefore, its conclusion of higher than before prevalence of depression and high anxiety level while incarcerated should be considered for diagnosis and therapy strategies in prison.