Background: Clarithromycin clinical efficacy has not been described in COVID-19. Research question: Is oral clarithromycin beneficial for treating patients diagnosed with COVID-19? Study and methods: An open-label non-randomized trial in 90 patients with COVID-19 of moderate severity was conducted at four study sites in Greece between May and October 2020. Ninety participants with respiratory tract infections received clarithromycin 500 mg every 12 hours for 7 days; another 90 standard-of-care (SOC) propensity score-matched concurrent controls received azithromycin plus hydroxychloroquine. The composite primary endpoint was defined for patients with upper respiratory tract infection as: (a) no need for hospital re-admission or (b) lack of progression into lower respiratory tract infection and, for patients with lower respiratory tract infection, as at least 50% decrease of the score of respiratory symptoms at the end-of-treatment (EOT) without progression into severe respiratory failure (SRF). The incidence SRF at the test-of-cure (TOC) on day 14 was a secondary endpoint. For clarithromycin-treated patients, viral load of SARS-CoV-2, biomarkers, the function of mononuclear cells, and safety were assessed; biomarkers were also measured in SOC comparators. Results: The primary endpoint was attained in 86.7% of patients treated with clarithromycin (95% CIs 78.1-92.2%) and 73.3% of concurrent SOC comparators (95%CIs; 63.4-81.4%). The odds ratio for the primary endpoint with clarithromycin treatment in univariate analysis was 2.36 (95%CIs 1.09-5.08; P: 0.039). Results were confirmed after multivariate stepwise logistic regression analysis (odds ratio 3.30; 95% CI 1.10-9.87; P: 0.033). At the TOC visit, the incidence of SRF was 12.2% (n = 11 ; 95%CIs 6.9-20.6%) among patients treated with clarithromycin (odds ratio for SRF 0.38; 95%CIs 0.17-0.84) versus 26.7% (n= 24; 95%CIs 18.6-36.6%) among concurrent SOC comparators (P: 0.023). Clarithromycin use was associated with decreases in circulating levels of C-reactive protein, of tumour necrosis factor-alpha and of interleukin (IL)-6; by an increase of the ratio of Th1 to Τh2 mononuclear responses; and by suppression of SARS-CoV-2 relative viral load. No safety concerns were reported. Patients starting clarithromycin with the first five days from symptoms onset achieved better responses. Interpretation: Clarithromycin treatment is associated with early clinical improvement in patients with moderate COVID-19. Modulation of the Th1/Th2 responses is proposed as the mechanism of action.