PURPOSE: Hypoglycaemia is a limiting factor for glycaemic management of diabetes with intensive insulin and/or oral antidiabetic drug (OAD) regimen. Case reports suggest that antidepressants may interfere with blood glucose metabolism in patients wth diabetes mellitus potentially increasing the risk of clinically relevant hypoglycaemia. Comorbid depression treated with antidepressants could therefore further complicate glycaemic control. We have carried out a nested case-control study among diabetic patients to assess the risk of hypoglycaemia requiring hospitalisation associated with the use of antidepressants. METHODS: Diabetic patients treated with insulin and/or OADs were selected from the Dutch Pharmo system. Exposure to antidepressants wasthe primary determinant investigated. Use of antidepressants was further subclassified based on the receptor binding profile to investigate whether specific pharmacological properties could explain a potential influence on glucose homeostasis. Conditional logistic regression was used to estimate odds ratios and to adjust for confounding factors. RESULTS: From the base cohort (40 600 patients), 549 (1.35%) cases were identified and 1897 controls were selected. Current use of any antidepressant was not associated with a significantly higher risk of hypoglycaemia requiring hospitalisation (OR: 1.36 (95%CI: 0.84-2.20)). A trend for a higher risk on hypoglycaemia was identified for antidepressants with high affinity for the serotonin reuptake transporter. The risk on severe hypoglycaemia was increased after 3 years of use (OR: 2.75 (95%CI: 1.31-5.77)). CONCLUSIONS: It is important for diabetic patients using antidepressants for more than 3 years to pay attention for symptoms of hypoglycaemia and strict blood glucose self-monitoring. Copyright (c) 2008 John Wiley & Sons, Ltd.