Effective therapeutic approaches for SARS-CoV-2 pandemic are urgently needed. Hydroxychloroquine (HCQ) alone or in combination with azithromycin has been used in several countries, without any clear evidence. This study aimed to determine the effectiveness and safety of hydroxychloroquine as compared to hydroxychloroquine and azithromycin combination in patients with COVID-19 pneumonia. This retrospective study evaluated all patients admitted to two university hospitals between 18 March and 20 May 2020 with the diagnosis of COVID-19 pneumonia. Out of 496 patients, 370 met the eligibility criteria and were included in the final analysis. The primary outcome was in-hospital mortality. Secondary outcomes were time to recovery, presence of severe acute respiratory infection (SARI), the requirement for oxygen therapy, and/or mechanical ventilation, length of hospital stay, and adverse events. A total of 222 patients received hydroxychloroquine and 148 were treated with HCQ and azithromycin combination. The in-hospital mortality rates were similar in the two groups (10.8% vs. 6.8%, respectively, p=0.186). Additionally, the needs for oxygen therapy, invasive mechanic ventilation (IMV) and intensive care unit (ICU) admission were not different. The rate of the requirement of non-invasive mechanic ventilation (NIV) was higher in patients receiving HCQ plus azithromycin (10.1% vs. 4.5%, p=0.035). Time to recovery was 3.5 days in HCQ and 5.0 days in HCQ plus azithromycin group (p<0.001). The median length of hospital stay was longer in patients with the combination therapy (7.0 vs. 5.5 days, p<0.001). Amongst all patients, only 3 patients developed electrocardiographic changes needing discontinuation of therapy. Observational design of the study is the main limitation. The present findings suggest that adding azithromycin to HCQ is not associated with any improvement in clinical outcome and mortality in patients with COVID-19 pneumonia and supports the current knowledge not to include azithromycin in the initial treatment of COVID-19.