To date, the only antiviral drug recommended for treating COVID-19 is remdesivir [3], although other antivirals are still under research [4]. In addition to remdesivir, tenofovir (as its prodrug tenofovir disoproxil fumarate, TDF) has shown clinical evidence in preventing COVID-19 morbidity in a retrospective observational study following HIV individuals under antivirals [5], and was associated with reduced mortality in a population cohort in South Africa [6]. Further an association with reduction in infection has been also reported [7]. Remdesivir and tenofovir were originally designed to inhibit the ATP polymerization into the growing nucleic acids chain respectively in a) the Ebola virus polymerase [8]and b) the HIV reverse transcriptase [9]. Remdesivir has been approved for treating COVID-19, based on its efficacy to prevent severe disease and reduce mortality [10]. On the other hand, evidence of the pre-exposure prophylactic efficacy of the nucleotide analogous tenofovir, in particular of TDF in combination with emtricitabine (FTC), has been suggested in an observational study evaluating SARS-CoV-2 infection outcomes among HIV patients under antiretroviral therapy in Spain [5]. Individuals taking TDF/FTC for their HIV infection showed significantly lower risk of SARS-CoV-2 infection and hospitalization compared with individuals taking other antivirals or taking the tenofovir-based prodrug tenofovir alafenamide fumarate (TAF) with FTC. A similar protective trend for TDF/FTC on COVID-19 mortality was observed in South Africa when compared to zidovudine or abacavir-based regimes [11]. Nevertheless, the findings on TDF still need to be confirmed by randomized clinical trials [12], and tenofovir-based therapies are not currently recommended for treating COVID-19. Worth noting, in vitro studies have shown contradictory evidence of the potential of TDF to inhibit SARS-CoV-2 replication at plausible therapeutic doses [13,14].