Post Kala-Azar Dermal Leishmaniasis (PKDL) is considered as a reservoir of visceral leishmaniasis (VL). It plays an important role in disease transmission. No satisfactory treatment regimen is available at present which is hundred percent safe and effective. Moreover, the parasite also shows a gradual increase in tolerance and resistance. This study evaluates the efficacy and safety of a novel combination, i.e. paromomycin plus miltefosine in the treatment of PKDL, which has not been tried previously. This is a pilot exploratory study. Thirty patients were enrolled in two groups. Group A (n=15) received two courses of paromomycin 11mg/kg/day IM  plus miltefosine 2.5 mg/kg/day orally (10 days) at fifteen-day interval, whereas group B (n=15) received three courses of  paromomycin plus miltefosine combination. The efficacy of these therapies were ascertained by the final parasitological cure at one year follow up. Lesion of the group A patients did not disappear completely at the end of therapy so all the patients were shifted to receive three courses of the same combination. All the thirty patients completed the study. Initial and Final parasitological cure was found to be 100% and 83.33% respectively. A total of 63 AEs were reported in 24 patients. All the AEs were CTC grade one. Pain at the site of injection (28.6%) was most commonly occurring AE and increase in hepatic enzymes level, eosinophilia, vomiting, gastritis etc. were among others. Efficacy of this novel combination therapy appears to be optimal with excellent safety and tolerability profile. Further studies with a higher number of samples are recommended.