Treatment of canine leishmaniasis (CanL) represents a challenge. Due to the high prevalence of renal disease associated to CanL, it is important to find an effective drug that does not damage the kidneys. Marbofloxacin has been shown to be effective and well tolerated in non-azotemic dogs with leishmaniasis. To evaluate the safety and efficacy of marbofloxacin in dogs with leishmaniasis and decreased renal function, 28 dogs suffering from leishmaniasis and chronic kidney disease (CKD) were treated with oral marbofloxacin at 2 mg/Kg/day for 28 days. During treatment dogs were assessed by performing weekly physical exams, measuring blood pressure and evaluating blood and urine parameters. Lymph node aspirations were also obtained at days 0 and 28. The global clinical score decreased significantly, from 6.2±3.4 to 4.7±3.1 (p = 0.0001), after treatment. Marbofloxacin also decreased parasitic load in 72% of the dogs. No significant differences in plasma creatinine, urine specific gravity, urinary concentrations of cystatin C, ferritin and urinary protein loss were detected during treatment. A transient but significant decrease in blood pressure was detected up to day 14 (from 180.1±36.6 to 166.0±32.7 mmHg; p = 0.016). Moreover, dogs showed a significant increase in plasma albumin concentration (from 15.0±5.2 to 16.6±3.9 g/L; p = 0.014) and a significant decrease in globulin concentration (from 59.0±18.1 to 54.1±18.0 g/L; p = 0.005). The results demonstrate that, in addition to being effective for treatment of CanL, marbofloxacin is a very safe drug in dogs with CKD and leishmaniasis.