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False-positive HIV-2 serology poses a diagnostic challenge, particularly in chronic infectious or inflammatory diseases that induce polyclonal B cell activation. Leprosy, caused by Mycobacterium leprae, is one such condition known to produce immunologic cross-reactivity with HIV antigens. We report the case of a woman in her seventh decade with multibacillary Hansen’s disease in a Type 1 (reversal) reaction who showed reactivity for HIV-2 antibodies on a fourth-generation chemiluminescent immunoassay despite having no risk factors for HIV-2 infection. She was clinically stable on multidrug therapy (MDT), and a confirmatory qualitative real-time PCR for HIV-2 RNA was negative, confirming a false-positive result. Laboratory tests showed mild anaemia and leucocytosis with normal hepatic and renal function. She was treated with corticosteroids while continuing MDT, with improvement over 3 weeks. This case highlights the need for confirmatory nucleic acid testing in hypergammaglobulinaemic states to avoid misdiagnosis, unnecessary therapy and social stigma.