OBJECTIVES To determine NutriQoL^® responsiveness and minimal clinically important difference (MCID) in patients receiving HEN. METHODS NutriQoL^®, a specific questionnaire, developed and validated in Spain, for the assessment of HRQoL in patients receiving HEN regardless of the underlying condition was administered to a prospective cohort from 4 Spanish hospitals. It includes 17 pairs of items of HEN-related HRQoL, scoring from -51 (worst HRQoL) to 51 (best HRQoL). NutriQoL^® was completed three times within 1-month (±15 days) intervals (visit 1/visit 2/visit 3). Responsiveness was assessed by estimating the effect size and the standardized response mean between visits 1 and 3. For MCID calculation an anchor-based approach was performed. Interquartile range of the change in NutriQoL^® from patients, who reported changes in their health-status (worse or better) between visits 2 and 3, was used. RESULTS A total of 86 subjects who presented clinical changes between visits [63% male; mean (SD) age 61 (13)] participated. Cancer was the main diagnosis leading to HEN prescription (66.3%). NutriQoL^® scores were 16.98 (14.57), 16.63 (14.86) and 18.92 (15.25) for visit 1, 2 and 3, respectively. Up to 78.79% of patients reported improvements in their HRQoL since the introduction of HEN. The estimated effect size and the standardized mean response between visit 1 and 3 were 0.23 and 0.24. Regarding MCID, NutriQoL^® total scores difference between visit 2 and 3 in those patients that perceived changes in their health status was between -3.75 and 4.25 (interquartile range). CONCLUSIONS NutriQoL^® responsiveness is moderate. This may be due to the limited temporal period between visits since most of patients referred improvements in their condition. A difference of ±4 points on NutriQoL^® total score regarding a previous administration demonstrates a clinical change that affects patients HRQoL.