Abstract: Acute angle-closure glaucoma (AACG) is an ocular emergency that may be precipitated by certain types of medications. Antidepressant drugs can affect a number of neurotransmitters, which are involved in the regulation of the iris, which may precipitate AACG. We used a case-crossover study design to investigate the association between recent exposure to antidepressant drugs and AACG. We identified patients with AACG among adults aged 66 years or older between 1998 and 2010 in Ontario using linked population-based administrative databases. We identified intermittent users of antidepressant medications through prescription drug claims in the year preceding AACG. We determined antidepressant exposure in the period immediately before AACG and compared it with antidepressant exposure in 2 earlier control periods. We used conditional logistic regression to determine the odds ratio for antidepressant exposure in the hazard period compared with the control periods. A total of 6470 patients with AACG occurred during the study period. The mean age of the patients was 74.3 years, and 66% were female. Overall, 5.6% of individuals were intermittent users of antidepressant drugs in the year preceding AACG. The odds ratio for any antidepressant exposure in the period immediately preceding AACG was 1.62 (95% confidence interval, 1.16–2.26). An increased risk of AACG was also observed in several subgroups. We conclude that recent exposure to antidepressant drugs is associated with an increased risk of AACG. Clinicians should remain vigilant for the development of this uncommon but potentially serious adverse event after initiating antidepressant therapy.