A human immunodeficiency virus (HIV)-seronegative woman was admitted to the hospital with postpartum onset Cryptococcus neoformans var. gattii meningitis and markedly increased intracranial pressure. A poor initial response to antifungal therapy was followed, 2 months after hospital admission, by severe acute meningeal and cerebral inflammation and clearance of yeast cells from cerebrospinal fluid. This first reported case of paradoxical inflammatory reaction to C. neoformans illustrates important aspects of the host-pathogen interaction and highlights possible effects of immunomodulatory therapies.