OBJECTIVES:  Conducting large studies in rare diseases is challenging. However, much valuable information can be obtained using qualitative and mixed-method approaches, such as in the case of acid sphingomyelinase deficiency (ASMD). ASMD, also called Niemann-Pick Disease Types A and B, is a rare, genetic, life-threatening condition with an estimated incidence of 0.4-0.6 per 100,000. There are significant unmet needs associated with this condition, and currently disease management is limited to symptomatic/palliative care only. The aim of this research was to address the lack of evidence about ASMD and specifically patients’ experiences of the condition. METHODS: A qualitative research study was conducted with 22 people with ASMD and/or their caregivers, to obtain information about the disease, its symptoms and impact. Participants were interviewed using open-ended questions and probes developed based on literature review and clinical expert interviews. Participants also completed symptom importance/bothersomeness ratings and questionnaires to characterize the sample. Results were also used to develop a conceptual disease model (CDM). RESULTS:  The mean (range) age was 37(18-63) years for adults and 10 (2-17) years for pediatric patients; 64% of adult and 45% of children were female. The most commonly reported symptoms were enlarged abdomen (due to hepatosplenomegaly), breathing difficulties, frequent respiratory infections, abdominal pain, bleeding/bruising, back and limb pain, and fatigue. Specific symptoms reported as being most bothersome included: fatigue, shortness of breath, bruising/bleeding, lower limb/joint pain, sleep disturbances, headaches, and diarrhea. ASMD was found to substantially impact physical, social, and emotional functioning in both adults and children. A CDM was developed and used to identify concepts most common and relevant to patients. CONCLUSIONS:  This study describes experiences of patients with ASMD and its significant impact on patients’ lives. The results can be used to support the development of ASMD disease-specific measures for the evaluation of patient-focused health outcomes in the condition.