Cryptococcus is normally described as a spherical encapsulated yeast of ~7 µm diameter, however under certain conditions cells can display considerable heterogeneity in size and shape. Giant cells >15 µm, micro cells < 2 µm, irregularly shaped cells, and cells with enlarged or shed capsule have been described in vivo and in vitro. There is conflicting data on whether these phenotypes enhance or reduce virulence and disease progression. This study examined the presence of morphological variants in two Cryptococcus collections: clinical isolates obtained from from HIV-AIDS patients in Botswana, and a set of strains derived over many years from the C. neoformans reference strain H99. Using conditions designed to simulate host infection, we assessed strains for the presence of cell morphotypes and correlated their presence with clinical and virulence data. Giant cells were on a spectrum of increasingly larger cells, while micro cells appeared to be an independent cell type and were strongly associated with the presence of extracellular capsule. In the Botswana clinical collection, the presence of larger cells and capsules was positively correlated with higher CD4+ T-cell count and negatively correlated with indicators of intracranial pressure, while micro cells and shed capsule had opposite associations, and in addition were negatively associated with indicators of cerebral inflammation. This suggests that larger cell types are more likely to occur in early stage infection when CD4+ count is still high and intracranial pressure is relatively low, with a transitions to smaller cell phenotypes as disease progresses, when micro cells and shed capsule may also act to dampen the host immune response. These findings were corroborated by the H99 derivative set, where strains that have been characterised as more virulent were the most abundant producers of micro cells and shed capsule. Taken together our analyses suggest that cell plasticity is important for virulence, can alter over the course of infection and is likely to be epigenetically determined.