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Current treatment options are plagued by toxicity, lengthy treatment regimens, and growing evidence of drug resistance. Immunotherapy, modulating the immune system to mount a protective response, may provide an alternate therapeutic approach. We investigated the ability of the Toll-like receptor 9 (TLR9) ligand CpG to modulate established disease in the<jats:italic>L<\/jats:italic>. (<jats:italic>V<\/jats:italic>.)<jats:named-content content-type=\"genus-species\">panamensis<\/jats:named-content>mouse model. Treatment of established infection with a high dose (50 \u03bcg) of CpG ameliorated disease and lowered parasite burden. Interestingly, immediately after treatment there was a significant increase in transforming growth factor \u03b2 (TGF-\u03b2) and concomitantly an increase in T regulatory cell (Treg) function. Although a general reduction in cell-mediated immune cytokine and chemokine (gamma interferon [IFN-\u03b3], interleukin 10 [IL-10], IL-13, IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-4, and MIP-1\u03b1) responses of the treated mice was observed, certain chemokines (RANTES, monocyte chemoattractant protein 1[MCP-1], and IP-10) were increased. Further, in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis, CpG treatment similarly exhibited a dose-response effect on the production of IFN-\u03b3, IL-17, IL-10, and IL-13, with reductions observed at higher doses. To further understand the underlying mechanisms and cell populations driving the CpG mediated response, we examined the<jats:italic>ex vivo<\/jats:italic>dose effects mediated by the TLR9<jats:sup>+<\/jats:sup>cell populations (dendritic cells, macrophages, and B cells) found to accumulate labeled CpG<jats:italic>in vivo<\/jats:italic>. Notably, B cells altered the production of IL-17, IL-13, and IFN-\u03b3, supporting a role for B cells functioning as antigen-presenting cells (APCs) and\/or regulatory cells during infection. Interestingly, B cells have been previously demonstrated as a primary type of APC in patients infected with<jats:italic>L<\/jats:italic>. (<jats:italic>V<\/jats:italic>.)<jats:named-content content-type=\"genus-species\">panamensis<\/jats:named-content>and thus may be useful targets of immunotherapy. Collectively, our results show that CpG-induced immune regulation leads to a dampening of the host immune response and healing in the mouse model, and it may provide an alternate approach to treatment of cutaneous leishmaniasis caused by<jats:italic>L<\/jats:italic>. 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