Abstract It has been speculated that some drugs can be used against SARS-CoV-2. As for antiretrovirals, the follow-up of pre-exposure prophylaxis (PrEP) users during the coronavirus disease 2019 (COVID-19) outbreak may help to understand the potential protective effect of PrEP against SARS-CoV-2. We aimed to identify associations between oral PrEP use and COVID-19-related symptoms self-reporting. Phone call interviews or digital investigation (through WhatsApp^® or e-mail) about oral PrEP regular use, social distancing, exposure to suspected or confirmed cases of SARS-CoV-2 infection and COVID-19-related symptoms. Among 108 individuals, the majority were cisgender, white and gay men. Although most of the individuals engaged in social distancing (68.52%), they kept on taking PrEP (75.93%). Few people have had contact with suspected or confirmed cases of COVID-19 (12.04%), but some had COVID-19-related symptoms the month before the interview (27.78%) including rhinorrheoa (56.67%), cough (53.33%), asthaenia (50.00%) and headache (43.33%). Also, oral PrEP was associated with lower self-reporting COVID-19-symptoms (OR 0.26, 95% CI 0.07–0.96, P = 0.04; h = 0.92) even after controlling confounders as social distancing, age, body-mass index and morbidities . In our sample, the regular use of oral PrEP was associated with lower self-reporting of COVID-19-related symptoms during the outbreak in São Paulo, Brazil.