Monkeypox (MPX) transmission outside non-endemic countries has been reported since May 2022, rapidly evolving into a multi-country outbreak. A potential role of sexual contact in transmission dynamics, as well as a predominance of anogenital lesions, are remarkable features of current cases. Screening for sexually transmitted infections (STIs) plays an important role in the evaluation of patients with suspected MPX infection. Herein we report the first case of a patient diagnosed with both MPX and acute HIV infection in Latin America. He had no major complications during his clinical course, and antiretroviral therapy was promptly initiated. Diagnosis of acute HIV requires a high level of suspicion and appropriate laboratory investigation. Health practitioners need to consider this diagnosis while evaluating patients with suspected MPX with a recent unprotected sexual contact. Conclusion: Considering acute HIV infection as a differential or even concomitant diagnosis during assessment of MPX suspected cases is of extreme importance. This might be challenging due to overlapping symptoms of these two infections and a potential common exposure, as epidemiological features of the current MPX outbreak points to a very frequent history of sexual contact. Our case report highlights the importance of MPX initial assessment as an opportunity to screen for other STIs, including acute HIV infection, reinforcing the need for a comprehensive sexual health assessment.