Autologous hematopoietic cell transplantation (AHCT) has presented a revolutionary advance in the management of hematologic malignancies with low toxicity. However, oral mucositis (OM) remains a distressing toxic effect of AHCT and one of the major side effects of the conditioning. This prospective, observational study aimed to evaluate the severity of oral cavity pain and quality of life (QOL) and explore incidence, duration, and potential risk factors of moderate/severe OM. Thirty-nine patients receiving prophylactic palifermin post-AHCT were enrolled. QOL and severity of pain were assessed using validated questionnaires (Functional Assessment of Cancer Therapy-General (FACT-G) and mouth and throat soreness (MTS), respectively). The incidence of moderate/severe OM was 28.2 % with a median duration of 5 days and was associated with younger age and female gender. Severity of pain related to OM was generally low or moderate with only 25 % of patients reporting a score >6 on the MTS scale of 0-10 on day +7. Health-related QOL was worse on day +7 in the transplant unit compared to day 1, while on discharge day, all scores recovered and the total FACT-G score was not different from that on day 1. In our population, the incidence and duration of OM and the severity of pain related to OM appeared to be lower compared to that reported in previous studies. The impact of OM on QOL assessments seemed to be reversible with optimal supportive care despite the major transient disabilities mainly attributable to OM.