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Abstract Introduction We sought to determine the effectiveness and safety of hydroxychloroquine–azithromycin (HCQ-AZM) therapy in hospitalized patients with COVID-19. Methods This was a retrospective cohort study of 613 patients hospitalized (integrated health system involving three hospitals) for RT-PCR-confirmed COVID-19 infection between March 1, 2020 and April 25, 2020. Intervention was treatment with HCQ-AZM in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Outcomes of interest were in-hospital all-cause mortality, cardiovascular mortality, pulseless electrical activity (PEA) arrest, non-lethal arrhythmias, and length of hospital stay. Secondary measures included in-hospital corrected QT (QTc) interval parameters and serum biomarkers levels. Results Propensity-matched groups were composed of 173 patients given HCQ-AZM and 173 matched patients who did not receive treatment. There was no significant difference in in-hospital mortality (odds ratio [OR] 1.52; 95% confidence interval [CI] 0.80–2.89; p = 0.2), PEA arrest (OR 1.68, CI 0.68–4.15; p = 0.27), or incidence of non-lethal arrhythmias (10.4% vs. 6.8%; p = 0.28). Length of hospital stay (10.5 ± 7.4 vs. 5.8 ± 6.1; p