Introduction Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein-1 (PLP-1) gene on the Xq22 chromosome affecting myelination of neurons. Clinical phenotype varies from mild motor deficits to severe spasticity and death at very young age. There is no definitive curative treatment. We report here a successful umbilical cord blood stem cell transplantation (UCBT) for PMD in a 2-year-old boy. Methods A 2-year-old Russian boy, first child of non-consanguineous parentage, presented to us with global developmental delay. Child had a history of prolonged seizures at 1½ yrs of age and was symptomatically managed in his native country. Subsequently child had total 5 episodes of right sided focal seizures. On examination, he had hypotonia and developmental delay with no evidence of dysmorphism or neurocutaneous markers. MRI brain revealed changes of leukodystrophy. CT scan head showed agenesis of corpus callosum & cerebellar vermis along with moderate ventriculomegaly. Genetic testing showed PLP-1 gene duplication. Child development quotient was approximately 70. He then underwent an UCBT from a 10/10 matched unrelated cord at our centre. Parents gave written informed consent before transplant. Myeloablative conditioning was used with Busulfan day-9 to -6 (3.2mg/kg/day), Cyclophosphamide day-5 to -2 (50mg/kg/day), Rabbit ATG day-3 to -1 (2.5mg/kg/day) and Rituximab on day-8 (100mg/m2). Cord blood stem cell (CD34+) dose was 0.2 million/kg. MMF and Cyclosporine were used for graft-vs-host disease (GVHD) prophylaxis. Results His neutrophil engrafted on day+29 and platelets on day+33. Post-transplant on day+30 he had reactivation of CMV and BK virus along with haemorrhagic cystitis which was managed successfully. On day+53, he had an episode of hematemesis and malena with sudden drop in hemoglobin. Upper and lower Gastrointestinal endoscopies were performed. Biopsies were suggestive of MMF induced enterocolitis which resolved after discontinuation of MMF. Chimerism on day+32, day+56 and day+100, 1-year and 2-years was fully donor. There was no evidence of acute or chronic GVHD. His further post-transplant period was uneventful. Neurodevelopmental assessment was done at 12 months and 24 months post-transplant which showed overall good improvement in all domain of developmental. His motor skills improved, he can walk independently and run for few meters with infrequent falls. Child could speak in sentences and better social communications skills. No further seizures were recorded post transplant. At present child is more than two years post-transplant and is doing fine. Conclusion PMD is a rare metabolic leukodystrophy with sparse treatment options. It appears that UCBT is feasible and beneficial treatment option for children with PMD.