Background: Surprisingly little is known about the burden of oral mucositis (OM). We provide a systematic review of studies on the burden of OM (incidence, economic impact, health-related quality of life (HRQoL)). Methods: Systematic literature searches were made in BIOSIS, EMBASE, and MEDLINE. Inclusion criteria were studies on OM in hematology/oncology patients of ≥ 18 years, journal articles, English language, and published between 2000 and 2016; OM treatment studies were excluded. Quality assessment was performed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We screened 4,996 hits, and identified 68 studies of which 13 were without transparency on OM grading. The evidence level of 65 studies was rated ‘low' or ‘very low' in 58.5%, ‘moderate' in 20% and ‘high' in 21.5%. Mean value of incidence (7 studies) was 83.5% for all grades of OM with hematopoietic stem cell transplantation. OM incidence for all grades in head and neck cancer patients was 59.4-100%. Considering the economic impact, 16 studies showed highly variable numbers. HRQoL was measured in 16 studies using 13 different instruments. Statistically significant changes in HRQoL scores were demonstrated. Conclusion: OM is common, burdensome, costly and imposes major reductions in HRQoL. However, from a quality standpoint, the level of current evidence in OM is disappointing. The field needs continued attention to address methodological challenges.