Cryptococcus neoformans is an encapsulated fungal pathogen that causes severe disease primarily in immunocompromised patients. Adherence and internalisation of microbial pathogens into host cells often begin with engagement of microbes to the surface receptors of host. However, the mechanisms involved remain poorly understood. In this study, we investigated the association of cell surface determinants of C. neoformans with mammalian cells. Our results showed that treatment with trypsin, but not paraformaldehyde or heat killing, could reduce host-cryptococci interaction, suggesting the involvement of cell surface proteins (CSPs) of C. neoformans in the interaction. We extended our investigations to determine the roles of CSPs during cryptococci-host cells interaction by extracting and conjugating CSPs of C. neoformans to latex beads. Conjugation of CSPs with both encapsulated and acapsular C. neoformans increased the association of latex beads with mammalian alveolar epithelial cells, alveolar macrophages and monocyte-derived macrophages. Further examination on the actin organisation of the host cells implied the involvement of actin-dependent phagocytosis in the internalisation of C. neoformans in CSP-conjugated latex beads. We hypothesised that CSPs present on the cell wall of C. neoformans mediate the adherence and actin-dependent phagocytosis of cryptococci by mammalian cells. Our results warrant further studies on the exact role of CSPs in the pathogenesis of cryptococcosis