BACKGROUND: Opium use in diabetic populations is associated with major depressive disorder (MDD). This study was designed to investigate the relationship between opium use and severity of depression in Iranian diabetic patients. METHODS: In this case-control study, 642 type 2 diabetic patients were recruited from those presenting at two outpatient clinics at the Akhavan Hospital in Kashan, Iran; of them, 600 diabetic patients were included in the study and divided into two groups: opium-abusers (150 patients) and non-opium-abusers (450 patients). Clinical and demographic information was obtained through a detailed questionnaire. Depression symptomalogy and severity were assessed with the Beck Depression Inventory (BDI), and a corresponding diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders-IV, Text Revision, 2000 (DSM-IV TR) criteria. RESULTS: The mean depression score was higher in the opium abuse group than in the non-abuser group (29.27+/-1.44 vs. 18.29+/-1.31, P<0.001). In general, a significant association was found between opium abuse and depression among patients (odds ratio [OR], 4.54; 95% confidence interval [CI], 2.87 to 7.44; P=0.001). No significant relationship was found between dysthymia and opium abuse (OR, 0.68; 95% CI, 0.18 to 1.192; P=0.155), while MDD was significantly higher in the opium abuser group (OR, 7.32; 95% CI, 5.20 to 12.01; P<0.001). CONCLUSION: Depression is more frequent in opium-dependent diabetic patients, and its severity is also greater. Given these findings, opium-dependent diabetic patients should be advised about the increased risks of depression and related comorbidities.