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Aim: To assess the efficacy and safety of hydroxychloroquine with or without azithromycin) in hospitalized adult patients with COVID-19. Methods: We utilized a hospital based prospective data registry. The primary end point was to assess the impact of hydroxychloroquine with or without azithromycin, on outcome, length of hospitalization, and time to clinical improvement. We utilized treatment effects with inverse-probability-weighting and Cox proportional hazards models. All analyses accounted for age, gender, race, severity on admission, days from symptoms onset and chronic comorbidities. Results: 36 patients received hydroxychloroquine and were age- and sex-matched to 72 patients with COVID-19 who received supportive care. Compared to supportive care, the use of HCQ did not shorten the time to clinical improvement (+0.23 days; 95% CI: −1.8–2.3 days) nor did it shorten the duration of hospital stay (+0.91 days; 95% CI: −1.1–2.9 days). Additionally, HCQ did not decrease the risk of COVID-19 in-hospital death (aHR 1.67; 95% CI: 0.29–9.36). Finally, we observed a slight QTc prolongation from a baseline of 444 ± 26 ms to 464 ± 32 ms (mean±SD) among patients receiving hydroxychloroquine with or without azithromycin. Conclusion: This study did not yield benefits from hydroxychloroquine use in patients with COVID-19 and monitoring for adverse events is warranted. Nevertheless, the treatment was safely studied under the guidance of an antimicrobial stewardship program.