Abstract Cryptococcus neoformans (C. neoformans) is an important cause of life-threatening opportunistic central nervous system (CNS) infection in HIV-1-infected patients. For areas of the world where HIV-1 is endemic, C. neoformans is the most common cause of culture-positive meningitis. Several lines of evidence from human cases and experimental animal models of C. neoformans CNS infection indicate that cerebral capillaries are the portal of C. neoformans entry into the brain. Since the entry of C. neoformans into the brain occurred in the cerebral microvasculature, we used the in vitro blood-brain barrier model with human brain microvascular endothelial cells (HBMEC) to investigate cryptococcal penetration of the blood-brain barrier. We showed that C. neoformans exhibited the ability to traverse the HBMEC monolayer in vitro and penetrate into the brain in vivo in the mouse model of experimental hematogenous C. neoformans CNS infection. The underlying mechanisms involved with C. neoformans penetration of the blood-brain barrier, however, remain incompletely understood. Our preliminary screen of HBMEC infected with C. neoformans for determination of host factors revealed globular C1q receptor (gC1qR). The role of gC1qR in C. neoformans penetration of the blood-brain barrier has not been previously recognized, and it remains unclear how gC1qR contributes to cryptococcus penetration of the blood-brain barrier. gC1qR is a multifunctional protein and shown to be expressed on the cell surface. We hypothesize that C. neoformans exploits gC1qR for penetration of the blood-brain barrier, the essential step in the development of cryptococcal CNS infection. This hypothesis is supported by our demonstration that HBMEC with gC1qR knockdown exhibited significantly less C. neoformans penetration. gC1qR does not have a consensus sequence of transmembrane domain, and the goal of this application is to elucidate how gC1qR contributes to C. neoformans penetration of the blood-brain barrier. The innovative aspect of this R21 exploratory application is to investigate a new target (gC1qR) exploited by C. neoformans for penetration of the blood-brain barrier. The information derived from this application will provide a new paradigm for investigating the pathogenesis of C. neoformans CNS infection.