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Cutaneous leishmaniasis (CL) affects the lives of 0.7–1 million people every year causing lesions that take months to heal. These lesions can result in disfiguring scars with psychological, social and economic consequences. Antimonials are the first line of therapy for CL, however the treatment is lengthy and linked to significant toxicities; further, its efficacy is variable and resistant parasites are emerging. Shorter or lower dose antimonial treatment regimens, which would decrease the risk of adverse events and improve patient compliance, have shown reduced efficacy and further increase the risk emergence of antimonial-resistant strains. The progression of lesions in CL is partly determined by the immune response it elicits, and previous studies showed that administration of immunomodulatory type D CpG ODNs, magnifies the immune response to Leishmania and reduces lesion severity in nonhuman primates (NHP) challenged with Leishmania major or Leishmania amazonensis. Here we explored whether the addition of a single dose of immunomodulating CpG ODN D35 augments the efficacy of a short-course, low-dose pentavalent antimonial treatment regimen. Results show that macaques treated with D35 plus 5mg/kg sodium stibogluconate (SbV) for 10 days had smaller lesions and reduced time to re-epithelization after infection with Leishmania major. No toxicities were evident during the studies, even at doses of D35 10 times higher than those used in treatment. Critically, pentavalent antimonial treatment did not modify the ability of D35 to induce type I IFNs. The findings support the efficacy of D35 as adjuvant therapy for shorter, low dose pentavalent antimonial treatment., Author summary Cutaneous leishmaniasis is a devastating disease that affects close to a million people every year. Its clinical presentation ranges from small uncomplicated lesions that heal over a few months to debilitating large chronic or recurring lesions that result in disfigurement, stigma, and economic loss. Antimonials are the first line treatment for cutaneous leishmaniasis in most countries, but the lengthy treatment schedules, significant associated toxicities, and the emergence of resistant strains, require the development of alternative strategies. As the immune response is a key determinant of disease course, immunomodulatory therapies could be harnessed to act in concert with antimonials to improve the safety and efficacy of CL treatment. Synthetic oligonucleotide D35 selectively activates plasmacytoid dendritic cells and was previously shown to reduce the severity of L. major and L. amazonensis lesions in rhesus macaques, but its activity in combination with antimonials was unknown. Our studies show that a single subcutaneous dose of innate immune modulator D35 improved the response to a low-dose abbreviated antimonial course, reducing the severity of the lesions and accelerating healing in primates. No toxicities were evident with D35 at doses ten-fold higher than the effective dose. The studies suggest that the combined therapy strategy shows clinical promise.