Background Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. Methods We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. Results The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. Conclusions Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials. Author summary Leishmaniasis, a neglected parasitic infection transmitted by the bite of a female sand fly, is endemic in 98 countries or territories with approximately 0.7 to 1.2 million cutaneous leishmaniasis (CL) cases occurring each year. In Panama, most of the CL cases are caused by L. panamensis and, the first line of treatment is pentavalent antimony, given parenterally for 20 days. These systemic regimen is associated with toxicities that can limit the patient from receiving a full course of treatment. Alternative therapies are needed particularly for patients with mild disease, no mucosal involvement, no immunosuppression, and for patients living in areas with scarce infrastructure. Therefore, less toxic, non-parenteral new therapies against CL are urgently needed. We conducted a comparative clinical study that evaluated Paromomycin topical creams (Paromomycin alone versus Paromomycin+Gentamicin) for the treatment of cutaneous leishmaniasis (n = 399) in three sites of country. Our study demonstrated the efficacy of these preparations against New World leishmanial species (mostly L. panamensis) with a cure rate close to 80%. Our trial supports Paromomycin as a viable alternative treatment for CL caused for the New World Leishmania species.