[Background] The prevalence of neuroAIDS and Cryptococcus neoformans meningitis has significantly increased and the mechanism remains unclear. [Objective] To study the inhibitory effect of SBi4211 on adhesion of C. neoformans to human brain microvascular endothelial cells (HBMEC) induced by HIV-1 gp41. [Methods] The adhesion experiments were carried out to determine whether SBi4211 could block C. neoformans adhesion. Furthermore, the expression of hyaluronic acid CD44 was analyzed by the Western Blot method (WB) during the adhesion process. [Results] SBi4211could significantly inhibit the HIV-1 gp41-enhanced adhesion of C. neoformans to HBMEC in a dose- and time-dependent manner (P<0.05). Meanwhile expression of the C. neoformans hyaluronic acid receptor CD44 on HBMEC is down regulated. [Conclusion] Our study suggested SBi4211 could block HIV-1 gp41-enhanced adhesion of C. neoformans to HBMEC by reducing expression of receptor CD44, which might provide novel insights into understanding the mechanisms of C. neoformans and HIV-1 associated comorbidity besides its prevention and treatment.