In previous studies we showed that a Cryptococcus neoformans mutant lacking glucosylceramide (Δgcs1) is avirulent and unable to reach the brain when it is administered intranasally into an immunocompetent mouse and is contained in a lung granuloma. To determine whether granuloma formation is key for containment of C. neoformans Δgcs1, we studied the role of C. neoformans glucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tgε26) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tgε26 mice infected with Δgcs1 do not produce a lung granuloma and that the Δgcs1 mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since Δgcs1 can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice Δgcs1 proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tgε26 mouse survival and decreased the dissemination of Δgcs1 cells to the central nervous system. Thus, these results suggest that the growth of Δgcs1 in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbate C. neoformans infection in conditions in which there is severe host immunodeficiency.