Cryptococcal meningitis is often associated with elevated IL-10 levels, which suggest a dysregulation in the antifungal immune response. beta-Arrestin 2 plays a major role in desensitization of G-protein-coupled receptors involved in the immune responses, provides a scaffolding platform for modification of many signal transduction proteins, and binds Src and MAP kinases family members. This study compared the levels of beta-arrestin 2 mRNA and protein in peripheral blood mononuclear cells (PBMC) of patients with cryptococcal meningitis detected. The interferon-gamma (IFN-gamma) serum concentration was determined with enzyme-linked immunosorbent assay (ELISA) to reveal its relationship with beta-arrestin 2. The effect of modulation of beta-arrestin 2 on cytotoxic activity against Cryptococcus was explored via transfection and interference of beta-arrestin 2. PBMCs of patients with cryptococcal meningitis exhibited significantly elevated levels of beta-arrestin 2 and a positive correlation between beta-arrestin 2 and IL-10 levels existed in patients' serum, but a negative correlation was found between beta-arrestin 2 and IFN-gamma expression. In conclusion, elevated expression of beta-arrestin 2 in PBMCs of patients with cryptococcal meningitis correlated with a reduced cytotoxic activity against Cryptococcus. This study suggests that reduced beta-arrestin 2 mRNA levels or inhibition of beta-arrestin 2 activity may augment INF-gamma production, and ultimately, the anti-Cryptococcus immune response of infected patients.