OBJECTIVES: The efficacy of different formulations of the naphthoquinone buparvaquone and two phosphate prodrugs in in vivo models of both visceral and cutaneous leishmaniasis is described. METHODS: Several topical formulations of buparvaquone containing acceptable excipients were tested in vivo against Leishmania major cutaneous lesions in BALB/c mice. In vivo studies against Leishmania donovani investigated whether the prodrugs had improved efficacy when compared with buparvaquone. RESULTS: Both a hydrous gel and water-in-oil emulsion of buparvaquone significantly reduced cutaneous parasite burden (P < 0.05, 22 days post-infection) and lesion size, compared with the untreated control (P < 0.0001, 16 days post-infection). The prodrug 3-phosphonooxymethyl-buparvaquone was formulated into an anhydrous gel and this also significantly reduced parasite burden and lesion size (P < 0.0001, 16 days post-infection). Histology confirmed this efficacy. In the visceral model, both prodrugs were significantly more effective at reducing liver parasite burden than the parent drug, buparvaquone. Buparvaquone-3-phosphate was shown to be the most effective antileishmanial (P = 0.0003, 50 mg buparvaquone molar equivalent/kg/day five times), reducing the liver parasite burden by approximately 34% when compared with the untreated control. CONCLUSIONS: The introduction of a topical formulation, such as buparvaquone (or its prodrug), would be a significant advance for the treatment of simple cutaneous lesions. In particular, the avoidance of the parenteral antimonials would greatly increase patient compliance and reduce treatment costs.