Cryptococcus neoformans is a fungal pathogen causing pulmonary infection and a life-threatening meningoencephalitis in human hosts. The fungus infects the host through inhalation, and thus, the host response in the lung environment is crucial for containment or dissemination of C. neoformans to other organs. In the lung, alveolar macrophages (AMs) are key players in the host lung immune response, and upon phagocytosis, they can kill C. neoformans by evoking an effective immune response through a variety of signaling molecules. On the other hand, under conditions not yet fully defined, the fungus is able to survive and proliferate within macrophages. Since the host sphingosine kinase 1 (SK1) regulates many signaling functions of immune cells, particularly in macrophages, in this study we determined the role of SK1 in the host response to C. neoformans infection. Using wild-type (SK1/2^+/+) and SK1-deficient (SK1^−/−) mice, we found that SK1 is dispensable during infection with a facultative intracellular wild-type C. neoformans strain. However, SK1 is required to form a host lung granuloma and to prevent brain infection by a C. neoformans mutant strain lacking the cell wall-associated glycosphingolipid glucosylceramide (Δgcs1), previously characterized as a mutant able to replicate only intracellularly. Specifically, in contrast to those from SK1/2^+/+ mice, lungs from SK1^−/− mice have no collagen deposition upon infection with C. neoformans Δgcs1, and AMs from these mice contain significantly more C. neoformans cells than AMs from SK1/2^+/+ mice, suggesting that under conditions in which C. neoformans is more internalized by AMs, SK1 may become important to control C. neoformans infection. Indeed, when we induced immunosuppression, a host condition in which wild-type C. neoformans cells are increasingly found intracellularly, SK1^−/− survived significantly less than SK1/2^+/+ mice infected with a facultative intracellular wild-type strain, suggesting that SK1 has an important role in controlling C. neoformans infection under conditions in which the fungus is predominantly found intracellularly.