The aim of this study was to compare the efficacy and safety of oral administration of miltefosine (Milteforan) at 2 mg/kg/day for 28 days (Group M; n = 60) with a subcutaneous administration of meglumine antimoniate (Glucantime) at 50 mg/kg/12 h or at 100 mg/kg/day for 28 days (Group G; n = 59) in the treatment of canine leishmaniosis in dogs. Out of 119 dogs included in the study, 90 could be used for efficacy assessment and 112 for safety assessment. Treated dogs were followed up for 6 weeks, with re-checks every 14 days. The mean total clinical scores significantly decreased throughout the study in both treatment groups. The evolution of parasitological results after treatment (D42) shows a high percentage of dogs with negative bone marrow smears, 90% and 91.3% in groups M and G respectively, and did not significantly differ between groups (p = 0.8066). Out of the 112 dogs used for the safety assessment, only 26 dogs (23.2%) presented product-related adverse events concerning the gastrointestinal tract. These results showed that miltefosine at 2 mg/kg once daily can be safely used over a 28-day period in the treatment of canine leishmaniosis and provides both a steadily increasing improvement of the clinical signs and a good leishmanicidal efficacy.