In murine histoplasmosis, tumor necrosis factor α (TNF-α) antagonism increases the number of regulatory T cells (Tregs) in lungs, and these cells profoundly hinder protective immunity. Because CCR5 mediates Treg homing and proliferation, we determined the outcome of antagonizing TNF-α in CCR5–/– mice infected with Histoplasma capsulatum. The absence of CCR5 attenuated the severity of infection associated with TNF-α neutralization. Infected controls given anti–TNF-α had a 10-fold increase in the number of Tregs in lungs compared with a <2-fold increase in CCR5–/– lungs. This difference was partially attributable to impaired homing in the absence of CCR5. Neutralization of TNF-α–enhanced CCR5 ligands in wild-type lungs thus promotes a gradient between lungs and the thymus. This study elucidates the interplay between TNF-α and CCR5 in histoplasmosis. The data suggest that targeting CCR5 may improve host immunity in individuals receiving TNF-α antagonists during infection.