Recently, there have been reports of false-positive HIV results associated with COVID-19 infections and vaccination, which require attention. The similarity between the spike proteins of HIV and SARS-CoV-2 may lead to cross-reactivity of antibodies, resulting in false-positive results on immunoassay screening tests. This hypothesis presents a serious diagnostic challenge. Patients presenting discordant COVID-19 and HIV results should undergo confirmation of the HIV chemiluminescent immunoassay due to the potential for analytical errors. It is essential to highlight the potential for false-positive HIV results related to SARS-CoV-2.