Abstract: Citation: Clin Transl Sci (2020) 13, 1071–1076; doi:10.1111/cts.12860 ARTICLE Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients With COVID-19 Marinella Lauriola1,†, Arianna Pani2,†, Giovanbattista Ippoliti3, Andrea Mortara4, Stefano Milighetti3, Marjieh Mazen3, Gianluca Perseghin3,5, Daniele Pastori6,*, Paolo Grosso7,‡ and Francesco Scaglione2,‡ Conflicting evidence regarding the use of hydroxychloroquine (HCQ) and azithromycin for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection do exist. We performed a retrospective single-center cohort study including 377 consecutive patients admitted for pneumonia related to coronavirus disease 2019 (COVID-19). Of these, 297 were in combination treatment, 17 were on HCQ alone, and 63 did not receive either of these 2 drugs because of contraindications. The primary end point was in-hospital death. Mean age was 71.8 ± 13.4 years and 34.2% were women. We recorded 146 deaths: 35 in no treatment, 7 in HCQ treatment group, and 102 in HCQ + azithromycin treatment group (log rank test for Kaplan–Meier curve P < 0.001). At multivariable Cox proportional hazard regression analysis, age (hazard ratio (HR) 1.057, 95% confidence interval (CI) 1.035–1.079, P < 0.001), mechanical ventilation/continuous positive airway pressure (HR 2.726, 95% CI 1.823–4.074, P < 0.001), and C reactive protein above the median (HR 2.191, 95% CI 1.479–3.246, P < 0.001) were directly associated with death, whereas use of HCQ + azithromycin (vs. no treatment; HR 0.265, 95% CI 0.171–0.412, P < 0.001) was inversely associated. In this study, we found a reduced in-hospital mortality in patients treated with a combination of HCQ and azithromycin after adjustment for comorbidities. A large randomized trial is necessary to confirm these findings. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ✔ Few clinical evidences are available regarding the use of hydroxychloroquine (HCQ) and azithromycin for patients with coronavirus disease 2019 (COVID-19), despite that this combination has been the most used worldwide so far. WHAT QUESTION DID THIS STUDY ADDRESS? ✔ This study evaluates the relationship between combination therapy of HCQ and azithromycin and in-hospital mortality in patients with severe acute respiratory syndrome coronavirus 2 infection-related pneumonia. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide since December 2019 and still no proven effective therapy has been found. First therapy proposed to treat coronavirus disease 2019 (COVID-19) has been the association of lopinavir-ritonavir, a protease inhibitor approved for HIV infection. However, Cao et al. observed no benefit comparing lopinavir-ritonavir treatment of hospitalized patients with severe COVID-19,1 and this treatment is currently not † WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ✔ This study reveals an inverse relation between HCQ and azithromycin use and in-hospital mortality, when compared with HCQ alone or no treatment. The combination was safe as patients with contraindications were excluded. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ✔ This efficacy analysis on a large sample that shows the potential efficacy of the combination of HCQ and azithromycin in COVID-19. recommended. Currently, only remdesivir has been approved for COVID-19 treatment, as it reduced recovery time by 4 days in..