Objective: To examine differences in mortality and/or severe acute respiratory syndrome between selective serotonin reuptake inhibitor- (SSRI) users and non-SSRI users up to 60 days after a positive SARS-CoV-2 real-time reverse transcription PCR test. Methods: Retrospective cohort study including all Danish residents above the age of eighteen with a positive SARS-CoV-2 PCR test from 26 February, 2020 to 5 October, 2021. The follow-up period was 60 days. The primary outcome was all-cause mortality, and the secondary outcome was severe acute respiratory syndrome. Exposure of interest was SSRI use. Differences between SSRI users and non-users were examined with Cox regression. Results: Altogether, 286,447 SARS-CoV-2 positive individuals were identified, and 7113 met the criteria for SSRI use. SSRI users had a mean age of 50.4 years, and 34% were males. Non-SSRI users had a mean age of 41.4 years, and 50% were males. Similar vaccination frequency was observed among the two groups. Sertraline was the most commonly used SSRI, followed by citalopram and escitalopram. We found 255 deaths among SSRI users (3.6%) and 2872 deaths among non-SSRI users (1.0%). SSRI use was significantly associated with increased mortality, with a hazard ratio of 1.32 (95% confidence interval, 1.16 –1.50; p 0.015), even when adjusting for age, sex, vaccination status, and comorbidities. Discussion: We found significantly higher mortality when comparing SSRI users to non-SSRI users within 60 days after a positive SARS-CoV-2 PCR test. Even when considering possible residual confounding, a positive effect of SSRI intake seems highly unlikely. Our study therefore speaks against the hypothesis of repurposing SSRI drugs for COVID-19 treatment.