Fungal pathogens Cryptococcus neoformans and the Cryptococcus gattii complex are responsible for hundreds of thousands of annual deaths. Cryptococcus is an encapsulated yeast, and during infection cells have the capacity for substantial phenotypic variation including capsule enlargement, the shedding of capsule, and variations in cell size. In order to examine associations between morphological variation and clinical outcome, we examined a collection of 70 clinical isolates of C. neoformans (n=53) and C. tetragattii (n=17) recently taken from HIV/AIDS patients with cryptococcal meningitis in Botswana with accompanying clinical data. Isolates were cultured under conditions that simulate stresses encountered in vivo (DMEM, 5% CO2, 37 °C) that are known to induce capsule production and cell size changes. Cells were counterstained with India Ink, visualised by microscopy, and phenotypes were scored and analysed for associations with clinical parameters using SPSS and R. Giant cells (> 15 μm) were significantly associated with C. tetragattii (p=0.007) while micro cells (< 1 μm) and shed capsule were only seen in C. neoformans isolates. When correlated with clinical data, phenotypic variables fell into two distinct groups associated with differing symptoms: the “big” phenotypes of bigger cells, bigger capsules, and giant cells, and the “small” phenotypes of micro cells and shed capsule. “Big” phenotypes were associated with higher CD4 count and were negatively correlated with nausea and vomiting (p=0.004), symptoms associated with increased intracranial pressure, suggesting that they are induced in early stage infection. “Small” phenotypes were associated with lower CD4 count, were negatively correlated with symptoms associated with meningeal inflammation, and were positively correlated with nausea and vomiting (p=0.015), suggesting that they are produced later during infection and may contribute to immune suppression and promote proliferation and dissemination of infecting cells. Strains possessing all three major morphological variants (giant cells, micro cells, and shed capsule) were rare, but strikingly these were associated with patient death (p=0.017). Our data indicate that the capacity to be highly pleomorphic is an important driver of infection and propose that this plasticity provides Cryptococcus with a “Swiss army knife” of virulence attributes that pre-adapt it for survival in a changing environment.