Visceral leishmaniasis (VL) is endemic in Asia, East and North Africa, South America, and Southern Europe, and is a major public health problem in the Indian subcontinent. Miltefosine received approval in 2002 to treat VL in India, and the Indian National Vector Borne Disease Control Programme later adopted a single dose (10 mg/kg) of liposomal amphotericin B. We report results of a randomized trial comparing the efficacy of combination therapy with an Indian preparation of liposomal amphotericin B (single dose of 7.5 mg/kg) and short-course miltefosine (2.5 mg/kg/day for 14 days; n = 66) in comparison to miltefosine monotherapy (2.5 mg/kg/day for 28 days; n = 78). Nine patients in the miltefosine group and three in the combination therapy group had to discontinue therapy because of serious adverse events. At the end of the therapy, the clinical and parasitological cure rate was 100% in both groups. By per-protocol analysis, by 6 months after completion of treatment, 12 of 69 patients in the miltefosine monotherapy arm (17.4%, 95% CI: 10.24-28%) and none in the combination therapy arm had relapse. Over 5 years of follow-up, 10 patients in the miltefosine monotherapy arm (all within 0.5-2 years after completing therapy) and none in the combination therapy arm experienced post-kala-azar dermal leishmaniasis. Combination therapy offered benefits over miltefosine monotherapy for VL in India.