The current study was performed to evaluate the effectiveness and safety of transdermal therapeutic system (TTS) fentanyl in the management of acute pain due to oral mucositis in patients receiving stem cell transplantation. A cohort of consecutive patients with painful oral mucositis were enrolled. Initially, 25 microg/h of TTS fentanyl was administered for the treatment of oral mucositis pain. The pain score, based on a visual analogue scale, and mood and quality of sleep as determined by EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Cancer 30), were all recorded before the treatment, then 2, 6, and 10 days later. Twenty-two patients with hematologic malignancies were enrolled. Three patients were excluded from the response assessment, as their TTS fentanyl treatment was stopped owing to related complaints, including severe dizziness, severe vomiting, and an extensive body rash. The total duration of the treatment was 8 days (range, 6-15 days) and the total amount of TTS fentanyl administered per patient was 2.21 at 25 microg/h and 0.63 at 50 microg/h. Six (31.6%) of the remaining 19 patients required an escalated dose of TTS fentanyl at 50 mug/h. The mean pain scores before treatment and 2, 6, and 10 days later were 6.68, 5.17, 3.42, and 2.13, respectively (P < .001). Eight (42.1%) and seven (36.8%) patients experienced improved sleep and mood after treatment, respectively. The TTS fentanyl was effective in both relieving oral mucositis pain with an excellent tolerability and improving the quality of life for hematological patients receiving high-dose chemotherapy with stem cell transplantation.