A unique occurrence of two subsequent episodes of HIV-associated Cryptococcus neoformans followed by C. laurentii meningoencephalitis (successfully cured with fluconazole after demonstrated amphotericin B resistance) is presented and discussed. The available literature reported only two cases of HIV-associated C. laurentii infection to date, while a concurrent infection by C. neoformans and C. laurentii has been reported only once in a patient without HIV disease. The absence of prior descriptions of documented central nervous system infection by C. laurentii in non-HIV-infected patients is emphasized as well as the unpredictable in vitro and in vivo antifungal susceptibility of this non-neoformans Cryptococcus spp., and its apparent prevalence in hospitalized patients who received prior antifungal treatments. All epidemiologic, diagnostic, clinical, and therapeutic implications are discussed on the basis of the evolving characteristics of opportunism in the era of highly active antiretroviral therapy (HAART).