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ObjectiveTo assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. DesignRetrospective cohort study. SettingAn analysis of data from electronic medical records and administrative claim data from the French Assistance Publique - Hopitaux de Paris (AP-HP) data warehouse, in 39 public hospitals, Ile-de-France, France. ParticipantsAll adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 2020 were eligible for analysis. The study population was restricted to patients who did not receive COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive drugs. End of follow-up was defined as the date of death, discharge home, day 28 after admission, whichever occurred first, or administrative censoring on May 4, 2020. InterventionPatients were further classified into 3 groups (i) receiving HCQ alone, (ii) receiving HCQ together with AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the 2 treatments (more or less one day). Main outcome measuresThe primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect (ATE) were computed to account for confounding. ResultsA total of 4,642 patients (mean age 66.1 {+/-} 18; males 2,738 (59%)) were included, of whom 623 (13.4%) received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. Patients receiving HCQ alone or HCQ plus AZI were more likely younger, males, current smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any chronic pulmonary diseases, liver diseases), while no major difference was apparent in biological parameters. After accounting for confounding, no statistically significant difference was observed between the HCQ and Neither drug groups for 28-day mortality AIPTW absolute difference in ATE was +1.24% (-5.63 to 8.12), ratio in ATE 1.05 (0.77 to 1.33). 28-day discharge rates were statistically significantly higher in the HCQ group AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). As for the HCQ+AZI vs neither drug, trends for significant differences and ratios in AIPTW ATE were found suggesting higher mortality rates in the former group (difference in ATE +9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to 1.81];p=0.062). ConclusionsUsing a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials. WHAT THIS PAPER ADDS?O_ST_ABSWhat is already known on this subjectC_ST_ABS- The use of Hydroxychloroquine (HCQ) or HCQ with azithromycin (AZI) has been associated with viral load reduction at 6 days in COVID-19 infected patients - No difference between HCQ and no-HCQ groups in terms of risk of death or need for mechanical ventilation was found in two large cohorts of hospitalized COVID-19 infected patients What this study adds- Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ on 28-day mortality - Our results suggest an excess risk of mortality in patients treated by a combination of HCQ and AZI, but not with HCQ alone - Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies