Importance: On the grounds of their anti-inflammatory and potential antiviral effects, we hypothesized that SSRIs and SNRIs might be effective treatments for Covid-19. Methods: We examined the association of antidepressant use with intubation or death in hospitalized patients with COVID-19. The primary endpoint was a composite of intubation or death in time-to-event analyses adjusted for numerous potential confounders. We compared this endpoint between patients who received antidepressants and those who did not. The primary analyses were multivariable Cox models with inverse probability weighting. Results: Of the 9,509 inpatients with positive Covid-19 RT-PCR test, 2,164 patients (22.8%) were excluded because of missing data or exclusion criterion (i.e. less than 18 years old of age). Of the remaining 7,345 adult inpatients, 460 patients (6.3%) received an antidepressant during the hospitalization. The primary endpoint occurred respectively in 143 patients exposed to antidepressants (31.1%) and 1,188 patients who were not (17.3%). After adjusting for the older age [74.8 (SD=15.5) versus 56.8 (SD=19.3); Welch9s t-test=23.7; p<0.001] and the greater medical severity of patients receiving antidepressants, the primary analyses showed a significant negative association of the composite endpoint with exposure to any antidepressant (HR, 0.64; p<0.001), SSRIs (HR, 0.56; p<0.001), and SNRIs (HR, 0.57; p=0.034), but not with other antidepressant classes. Exposure to escitalopram, fluoxetine, and venlafaxine was significantly associated with lower risk of intubation or death (all p<0.05). Results were similar in multiple sensitivity analyses. Conclusions: SSRIs and SNRIs may be associated with lower risk of death or intubation in patients with COVID-19.