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Oleylphosphocholine (OlPC) is a miltefosine derivative that is more effective than miltefosine against Leishmania infections in rodent models. Because canines are a natural host for Leishmania, the improved treatment of canine leishmaniasis is essential both for veterinary medicine and as a large animal model for clinical development. Oleylphosphocholine, at a dosage of 4 mg/kg/day for 28 days, was compared with the approved canine regimen of miltefosine at a dosage of 2 mg/kg/day for 28 days in 33 naturally infected Brazilian dogs (17 randomly assigned to receive OlPC versus 16 designated to receive miltefosine). The animals were followed for 5 months posttreatment. The primary endpoint was the clinical score, which was calculated as the sum of scores for each of 23 clinical parameters graded 0 (normal), 1 (somewhat abnormal), or 2 (markedly abnormal) by a blinded observer. A higher clinical score signified more severe disease. The mean (SD) clinical scores for the OlPC versus miltefosine groups are as follows: pretherapy, 10.1 (5.6) versus 7.7 (4.5; P = 0.19); 3 months posttherapy, 4.3 (4.1) versus 9.5 (4.9; P <0.01); 5 months posttherapy, 3.9 (3.8) versus 8.9 (4.7; P <0.01). Scores for lymph nodes, ear crusts, and splenic parasites were statistically lower for the OlPC group versus the miltefosine group, suggesting that both visceral and cutaneous parameters contributed to OlPC's statistically greater efficacy. One OlPC animal, with minimal splenic parasites pretreatment and zero parasites at the end of treatment, died of kidney failure due to immune-complex deposition, which was presumably already present pretreatment. The increase in blood creatinine values observed in OlPC animals warrants further study in future experiments. The superior clinical effect of OlPC in comparison to miltefosine in this canine study primes OlPC for development as an oral treatment for canine and human leishmaniasis.