BACKGROUND: Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients affected suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific instrument to measure health-related quality of life (HRQoL) impairment in patients with mastocytosis. OBJECTIVE: The aim of this study was to develop and validate a disease-specific tool to assess HRQoL impairment in patients with cutaneous and indolent systemic mastocytosis, the Mastocytosis Quality of Life Questionnaire (MC-QoL). METHODS: Sixty-two potential MC-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients and a final review for face validity. The resulting MC-QoL was tested for validity, reliability and influence factors. In parallel, an US American-English version of the MC-QoL was developed. RESULTS: A total of 158 patients (41 CM, 41 MIS and 76 ISM) took part in the MC-QoL validation study. The final 27-item questionnaire was found to have a four-domain structure ('symptoms', 'emotions', 'social life/functioning' and 'skin'), a valid total score and an excellent test-retest reliability. Multiple regression analysis revealed disease duration, but not age, gender or skin involvement to be a significant determinant of HRQoL impairment in mastocytosis. CONCLUSIONS: The MC-QoL is the first disease-specific HRQoL questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This short, validated and reliable instrument will serve as a valuable tool in future clinical studies and in routine patient care.