Purpose <p>Short bowel syndrome with intestinal failure (SBS-IF) requires lengthy parenteral support (PS) infusions to maintain nutrition and hydration, and may also involve treatment with glucagon-like peptide 2 (GLP-2) analog injections. SBS-IF and its treatment have significant health-related quality-of-life (HRQoL) impacts on patients. While existing patient-reported outcome (PRO) questionnaires measure HRQoL impacts of SBS, differences in intestinal anatomy or treatment type have their own impacts to patients that warrant assessment. This qualitative research supports the content validity of three new questionnaires to measure these specific impacts on&#xa0;patients with SBS-IF (i.e., questionnaires are measuring what is important in ways that are understandable to patients).</p> Methods <p>Qualitative research activities, including a targeted literature review, meetings with clinical experts, and patient interviews, were conducted to understand the patient experience of SBS-IF and its treatment and to inform the development and evaluation of questionnaires to measure HRQoL impacts related to patients with jejunostomy (‘stoma’); patients with colon-in-continuity and no stoma (‘CIC’); and PS infusions and GLP-2 analog injections for both groups of patients.</p> Results <p>From the publications (<i>n</i> = 26), and meetings with experts (<i>n</i> = 8), three draft questionnaires were constructed for impacts specific to SBS-IF with stoma, impacts specific to SBS-IF with CIC, treatment impacts related to PS infusions&#xa0;and GLP-2 analog injections. Qualitative patient interviews (<i>n</i> = 23) confirmed the questionnaires’ relevance and comprehensibility; minor revisions were subsequently made to the questionnaires based upon participants’ suggestions.</p> Conclusion <p>This research provides content validity evidence for the three questionnaires to measure HRQoL impacts of SBS-IF, PS infusions, and GLP-2 analog injections among patients with SBS-IF.</p>