This study aimed to evaluate the efficacy and toxicity of tenofovir (TDF) and TDF combined with emtricitabine (TDF/FTC) in patients with mild to moderate COVID-19 infections. We conducted a randomized, double-blind, placebo-controlled clinical trial in patients with clinical suspicion of mild to moderate respiratory infection caused by SARS-CoV-2 who were treated at an outpatient clinic. Patients were randomly recruited to take 10 days of TDF (300 mg/day), TDF (300 mg/day) combined with FTC (200 mg/day) or placebo Vitamin C (500 mg/day). The primary parameter was the score of symptoms and predictive signs of COVID-19, assessed on the seventh day of patient follow-up. From a total of 309 patients with clinical suspicion of SARS-CoV-2, 227 met the inclusion criteria and were randomly distributed into the following groups: (a) 75 (one did not initiate treatment) in the TDF group; (b) 74 in the TDF combined with FTC group; and (c) 77 in the Vitamin C group (placebo). Of the 226 patients, 139 (62%) were positive for SARS-CoV-2. Fever (37.8oC), ageusia or dysgeusia, anosmia or dysosmia, and two or more clinical symptoms or signs were significantly associated with SARS-CoV-2 infection. There was no significant change in clinical score based on clinical symptoms and signs between treatment groups. Patients with mild to moderate infection by SARS-CoV-2 had higher concentrations of G-CSF, IL-1β, IL-6 and TNF-α compared to patients without infection. Patients with mild to moderate respiratory infection, with fever (37.8oC), loss of smell, loss of taste and two or more symptoms, have a better prediction for the diagnosis of COVID-19. Patients with SARS-CoV-2 showed higher and more persistent proinflammatory cytokines profile compared to patients not infected with SARS-CoV-2. Pharmacological intervention with TDF or TDF combined with FTC did not change the clinical signs and symptoms score in mild to moderate respiratory infection in patients with SARS-CoV-2 compared to the Vitamin C group (placebo).