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Despite the wide use of antiretroviral therapy (<jats:styled-content style=\"fixed-case\">ART<\/jats:styled-content>) resulting in a declined prevalence,<jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>remains the most common oral lesions seen in those living with<jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">AIDS<\/jats:styled-content>. Various topical and systemic antifungal drugs are available to treat<jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>. However, due to the patients\u2019 immunodeficiency and the nature of<jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>as biofilm\u2010associated infection, relapse is frequently observed after cessation of antifungal therapy. In addition, long\u2010term antifungal therapy may lead to drug resistance. This review article addressed three major challenges in the treatment of<jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>in<jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>infection including antifungal drug resistance, biofilm\u2010associated infection of<jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>, and the host underlying immunodeficiency. To reduce the risks of antifungal drug resistance, the author recommends that future studies should focus on herbal plant\u2010derived compounds with antifungal activity that may be used in combination with the drugs. 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