Background: Patient-reported outcome (PRO) instruments collect information from patients about health conditions and disease management, including quality of life (QOL). Clinicians acknowledge patient concerns about QOL but need guidance to assess the nature and severity of individually experienced problems. The Home Parenteral Nutrition (HPN)–Patient-Reported Outcome Questionnaire (PROQ) was developed for use during medical appointments or homecare visits to address this gap. The purpose of this research was to provide evidence that the HPN-PROQ items and scale possess content validity. Methods: A mixed-method study design was used. In phase 1, cognitive interviews (CIs) were conducted with 32 HPN patients. Thematic analysis was used to assess participant understanding of the instructions, items, and response scales and overall utility of the HPN-PROQ. In phase 2, 13 expert clinicians evaluated the relevance of items to the HPN population using the Content Validity Index (CVI) to produce item-level (I-CVI) and scale-level (S-CVI) scores. Items with an I-CVI score ≥0.783 were retained. Results: Fifty-four percent of items were deemed as being comprehensible, acceptable, and clear; 25% were revised; and 11% were deleted. In phase 2, 79% of items were rated highly relevant. The S-CVI score was 0.96. The final HPN-PROQ contains 34 items. Conclusion: This study established acceptable content validity of the HPN-PROQ. This PROQ may help foster patient-clinician communication about lifestyle adaptation and QOL.