Background: Selective serotonin reuptake inhibitors (SSRIs) use may be associated with development of subdural hematoma (SDH). Objectives: To estimate SDH risk associated with antidepressant use, including when combined with antithrombotics, or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients/Methods: We performed this case-control study based on Danish registries. We included 10 885 incident cases of SDH and 435 379 matched general population controls. We calculated odds ratios (95% confidence interval) adjusted for comorbidity, co-medication, education level, and income (aOR). Results: We found that current use of SSRIs (aOR1.32 [1.25-1.38]) and non-SSRIs (aOR 1.19 [1.13-1.26]) was associated with a higher SDH risk, compared with non-use of antidepressants. Risks were higher with short duration of current use (eg, <1 month of current use: aOR 2.55 [2.07-3.15] for SSRI, 1.88 [1.46-2.41] for non-SSRIs; >3 years of current use: 1.04 [0.93-1.17] for SSRI and 1.12 [0.98-1.28] for non-SSRIs). Combined use of antidepressants with either antithrombotics or NSAIDs yielded similar ORs to those observed for single use of antithrombotics or NSAIDs. Stronger associations were observed for antidepressants combined with both vitamin K antagonists (VKAs) and NSAIDs (SSRI, VKA, & NSAID: aOR 5.51 [2.70-11-22]; non-SSRI, VKA, & NSAID: 6.81 [2.37-19-60]). Conclusions: Antidepressant use was associated with higher risk of SDH that seemed largely restricted to first year of treatment. In absolute terms this risk is judged to be small, given the low SDH incidence rate. With one possible exception (triple use of antidepressants, NSAIDs, and VKAs), risk estimates of SDH for combined regimens of antidepressants with antithrombotics or NSAIDs provided little evidence of interactions.