The role of hydroxychloroquine (HCQ) in lowering the viral load of patients with COVID-19 is controversial. In our Institute, we treated more than 30,000 people with COVID-19 in 2020 and 2021, using the same diagnostic tools and the same treatment dosages. In this retrospective comparative study of data collected over this period, we aimed to compare the viral clearance in the nasopharynx as determined by qPCR in patients who were treated with HCQ and those who were not. As a new feature, we adjusted the data according to the most significant confounding factors (age, initial viral load, and timescale between the onset of symptoms and treatment). Of the 1 276 patients selected from our database, 776 were treated with HCQ and 500 were not. Viral clearance in the treatment group was reached significantly earlier than in the non-treatment group, at days 5, 10 and 30. These differences remain significant after adjustments for confounding factors. In conclusion, although age, initial viral load, and time to treatment do influence the viral load in patients with COVID-19, hydroxychloroquine associated with azithromycin still independently significantly lowered viral load more rapidly than other treatments, including azithromycin alone.