Background <p>Despite the expansion of antiretroviral treatment programmes, the incidence and mortality of HIV-associated cryptococcal meningitis remain high in Africa. Cryptococcal antigen (CrAg) in the blood precedes meningitis. CrAg screening of individuals with advanced HIV disease, combined with pre-emptive fluconazole treatment, reduces the risk of cryptococcal meningitis and associated mortality. However, mortality among individuals with antigenaemia treated with fluconazole is higher than that of CD4-matched individuals with a CrAg-negative test. Autopsy studies have found that cryptococcal disease remains an important cause of death in people with antigenaemia despite pre-emptive antifungal treatment. This suggests a need for more potent treatment for antigenaemia. Flucytosine, combined with fluconazole, is an effective and safe oral treatment for cryptococcal meningitis, and flucytosine has become more widely available as a generic formulation. This trial aims to determine whether combination treatment of fluconazole plus flucytosine is superior to fluconazole monotherapy in reducing all-cause mortality among adults with antigenaemia without evidence of meningitis.</p> Methods <p>This multi-centre, open-label phase III randomised-controlled trial embedded in routine CrAg screening programmes in South Africa and Tanzania will compare 14 days of fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day) to fluconazole (1200 mg/day) alone for the treatment of adults with advanced HIV disease, a blood CrAg-positive test and without evidence of meningitis. Following this 2-week induction therapy, all participants are given fluconazole consolidation and maintenance therapy per local guidelines. The primary endpoint is all-cause mortality at 6 months (superiority analysis). Secondary endpoints include time to all-cause mortality, cryptococcal meningitis-free survival and incidence of symptomatic cryptococcal meningitis, proportion of participants with grade 3 or 4 adverse events, efficacy outcomes by baseline CrAg titre/CrAg semi-quantitative assay score, and health service and household costs per life year saved. A total of 600 participants will be enrolled, 300 per arm, sufficient to detect a 40% relative reduction in mortality with 91% power.</p> Discussion <p>An all-oral combination regimen of flucytosine with fluconazole, tested in adults with early cryptococcal disease across a range of baseline CrAg titres, could be an easy-to-administer, safe, and implementable alternative if found to be superior to the current World Health Organization recommended standard of fluconazole monotherapy.</p> Trial registration <p>ISRCTN30579828, registered 04 March 2021, and SANCTR DOH-27-122021-6511, registered 06 December 2021.</p>