OBJECTIVE: Diabetes type 2 is associated with depression, but the impact of antidiabetic drugs is not clear. The objective was to analyze the association between diabetes type 2, antidiabetic drugs, and depression. METHODS: This register-based study included 116.699 patients with diabetes type 2 diagnosed from 2000 to 2012 and an age, gender, and municipality matched reference group of 116.008 individuals without diabetes. All participants were followed for a diagnosis of depression or prescription of antidepressant medication. Based on this, a case-control study was nested within the cohort, using risk set sampling. Antidiabetic medication was categorized into insulin, metformin, sulfonylureas and glinides combined, glitazones, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose. The association between diabetes and depression was analyzed using Cox proportional hazards regression, whereas conditional logistic regression was used to analyze the association between use of antidiabetic drugs and depression. RESULTS: Patients with diabetes had higher risk of depression compared to individuals without diabetes (hazard ratio 1.14 (95% confidence interval 1.14-1.15)). Low doses of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower risk of depression in patients with diabetes compared to non-users, with the lowest risk for sodium-glucose transport protein 2 inhibitor users (odds ratio 0.55 (0.44-0.70)). Use of insulin, sulfonylurea and high doses of metformin were associated with higher risk of depression. CONCLUSION: Patients with diabetes had increased risk of depression. However, users of specific antidiabetic drugs had lower risk of depression compared to non-users.