Objective Conditioning regimens for hematopoietic stem cell transplantation (HSCT) are well known to cause severe gastrointestinal toxicities that often disturb the oral intake of the patients followed by poor nutrition and life-threatening infection. An oral elemental diet (ED) is an easily consumed and assimilated form of liquid nutrients mainly composed of amino acids. It alleviates the digestive loading from the intestine and is mainly used for enteral nutritional support in patients with Crohn's disease. We herein report, for the first time, the efficacy of ED for patients undergoing HSCT. Methods We evaluated the efficacy of ED in a prospective cohort study. The primary endpoint for this study was the hospitalization period. The secondary endpoint was the occurrence of oral mucositis, nausea, diarrhea and fever. Patients A total of 73 patients were consecutively enrolled between March 2011 and March 2013. Twenty-three patients underwent autologous HSCT and 50 patients underwent allogeneic HSCT. The first 21 patients did not receive ED (non-ED group; NEG) while in the successive 52 patients (ED group; EG), oral ED was started before conditioning and was continued until 28 days after transplantation. Results The patient characteristics were similar between the two groups. The mean duration of ED administration for EG was 28.7 days (range, 3-37 days), and the mean total-dose of ED administration was 1904 g (range, 240-2,960 g). The median hospitalization period was significantly shorter in EG compared to NEG, (34 days vs. 50 days; p=0.007). Grade 3-4 oral mucositis occurred less in EG than NEG (25% vs. 48%; p=0.06). Conclusion Oral ED may promote an early mucosal recovery and thereby shorten the duration of hospitalization.