Pulmonary clearance of the encapsulated yeast Cryptococcus neoformans is associated with the CCR2-mediated accumulation of lung dendritic cells (DC) and the development of a T1 adaptive immune response. The objective of this study was to identify the circulating DC precursor(s) responsible for this large increase in lung DC numbers. An established murine model was used to evaluate putative DC precursors in the blood, bone marrow, and lungs of CCR2(+/+) mice and CCR2(-/-) mice throughout a time course following infection with C. neoformans. Results demonstrate that numbers of Ly-6C(high) monocytes increased in parallel in the peripheral blood and lungs of CCR(+/+) mice, whereas CD11c(+) MHC class II(+) pre-DC were 10-fold less prevalent in the peripheral blood and did not differ between the two strains. Accumulation of Ly-6C(high) monocytes correlated with a substantial increase in the numbers of CD11b(+) DC in the lungs of infected CCR2(+/+) mice. Comparative phenotypic analysis of lung cells recovered in vivo suggests that Ly-6C(high) monocytes differentiate into CD11b(+) DC in the lung; differentiation is associated with up-regulation of costimulatory molecules and decreased Ly-6C expression. Furthermore, in vitro experiments confirmed that Ly-6C(high) monocytes differentiate into CD11b(+) DC. Accumulation of Ly-6C(high) monocytes and CD11b(+) DC was not attributable to their proliferation in situ. We conclude that the CCR2-mediated accumulation of CD11b(+) DC in the lungs of Cryptococcus-infected mice is primarily attributable to the continuous recruitment and differentiation of Ly-6C(high) monocytes.