Osteoprotegerin (OPG) prevents binding of receptor activator of nuclear factor-kappa B ligand (RANKL) to RANK. Recent studies have reported that immune cell RANK-RANKL interactions are critical to the infection process. Candida albicans is an opportunistic pathogenic fungus and a common cause of candidiasis. This study utilized an orally inoculated mouse model of C. albicans infection to determine whether superficial or systemic candidiasis was associated with alterations in RANK/RANKL/OPG expression. Invasive systemic C. albicans infection increased serum OPG levels in mice. In addition, tongue Opg, Rankl, and Rank mRNA expression were upregulated in mice with superficial oral cavity C. albicans infection. Moreover, administration of exogenous soluble RANKL upregulated Rank and interleukin-10 (Il-10) mRNA in superficially infected tissue, suggesting suppression of localized inflammation. Taken together, these findings suggested that RANK/RANKL/OPG signaling contributes to the pathogenesis of candidiasis. This is the first in vivo study to identify a relationship between this opportunistic infection and the RANK/RANKL/OPG axis.