When Acute Epstein-Barr Virus Mimics HIV: A Case of False-Positive p24 Antigen and Low-Level HIV Antibody Reactivity

False-positive HIV screening results are uncommon but clinically significant, often leading to patient anxiety and diagnostic uncertainty. Acute Epstein-Barr virus (EBV) infection is a recognised but rare cause of cross-reactivity with fourth-generation HIV assays, particularly p24 antigen and low-level HIV antibody reactivity. We report a 57-year-old male with a history of hypothyroidism and atrial fibrillation who presented with sore throat, tender cervical and occipital lymphadenopathy, diffuse rash, dark urine, and fatigue. Initial investigations showed lymphocytosis and marked transaminitis. Fourth-generation HIV testing was repeatedly reactive, with positive p24 antigen and low-level HIV-1/2 antibody reactivity across three separate samples. In contrast, HIV-1 RNA and HIV-2 RNA viral loads were consistently undetectable (<20 copies/mL). EBV serology demonstrated viral capsid antigen (VCA) IgM positivity with transient EBV DNA detection, and the clinical presentation was consistent with acute EBV infection. Additional viral serologies, including cytomegalovirus (CMV), varicella-zoster virus (VZV), measles, parvovirus, and syphilis, were negative. Monkeypox PCR was weakly positive once but negative on repeat testing. The patient's wife, who was pregnant, tested negative for HIV. He improved with supportive care, and follow-up demonstrated normalisation of liver function tests and persistently negative HIV serology, confirming a false-positive HIV result in the setting of acute EBV infection. This case is significant because it illustrates a rare but important diagnostic pitfall: acute EBV infection mimicking acute HIV. The implications of a false HIV diagnosis are profound, carrying psychological, social, and clinical consequences, heightened in this case by the patient's pregnant wife. The discrepancy between reactive screening assays and undetectable HIV-1 and HIV-2 RNA underscores the importance of confirmatory testing and clinical correlation. Clinicians should be aware that acute EBV infection may result in false-positive HIV p24 antigen and antibody reactivity. Reporting such cases adds to the limited literature and serves as an important reminder to interpret discordant HIV results with caution to avoid misdiagnosis and unnecessary psychological burden.