Background: Although fatigue is one of the most common symptoms of multiple sclerosis (MS) and several patient-reported outcome (PRO) instruments assess MS-related fatigue, few PROs include the perspective of progressive MS (PMS) patients in their development. Objectives: This qualitative study was conducted to understand fatigue in a PMS population and evaluate the conceptual frameworks of existing MS-specific PROs for use in this population. Methods: A previous targeted literature review identified MS-specific fatigue PROs. A discussion guide was developed with the concepts from these PROs. Following IRB approval and consent, adult PMS subjects who reported MS-related fatigue in the last 6 months were individually interviewed to elicit MS-related fatigue concepts. Data were analyzed and compared to concepts in existing PRO instruments to evaluate their relevance in a PMS population. Results: Of the 30 PMS subjects that participated, 70% were female, mean age was 51 years [range 3275 years] and 47% were primary PMS, 33% were active secondary PMS, and 20% were non-active secondary PMS. All participants reported fatigue had physical components, described commonly as feeling tired, weak, exhausted, or having low energy. Most participants (80%) noted fatigue had mental components including difficulty communicating, concentrating, or focusing. When comparing the qualitative interview findings to the concepts in the identified MS-specific fatigue PROs, the fatigue symptoms and impacts questionnaire (FSIQ-RMS) was the most suitable to PMS individuals as concepts in the qualitative research aligned with the FSIQ-RMS items. The modified fatigue impact scale (MFIS) was deemed suitable contingent on modifications. Other identified PRO instruments have low suitability as they omit key concepts and/or do not distinguish between mental and physical aspects of fatigue. Conclusions: This qualitative study provides meaningful physical and mental concepts of fatigue in a PMS population and preliminary support of the appropriateness of the FSIQ-RMS in assessing fatigue in PMS patients.