The opportunistic fungus Candida albicans is one of the leading causes of infections in immunocompromised patients, and innate immunity provides a principal mechanism for protection from the pathogen. In the present work, the role of integrin α(X)β₂ in the pathogenesis of fungal infection was assessed. Both purified α(X)β₂ and α(X)β₂-expressing human epithelial kidney 293 cells recognized and bound to the fungal hyphae of SC5314 strain of C. albicans but not to the yeast form or to hyphae of a strain deficient in the fungal mannoprotein, Pra1. The binding of the integrin to the fungus was inhibited by β-glucans but not by mannans, implicating a lectin-like activity in recognition but distinct in specificity from that of α(M)β₂. Mice deficient in α(X)β₂ were more prone to systemic infection with the LD₅₀ fungal inoculum decreasing 3-fold in α(X)β₂-deficient mice compared with wild-type mice. After challenging i.v. with 1.5 × 10⁴ cell/g, 60% of control C57BL/6 mice died within 14 d compared with 100% mortality of α(X)β₂-deficient mice within 9 d. Organs taken from α(X)β₂-deficient mice 16 h postinfection revealed a 10-fold increase in fungal invasion into the brain and a 2-fold increase into the liver. These data indicate that α(X)β₂ is important for protection against systemic C. albicans infections and macrophage subsets in the liver, Kupffer cells, and in the brain, microglial cells use α(X)β₂ to control fungal invasion.