Home enteral nutrition (HEN) is recommended for patients with nutritional requirements who can stay in the familiar environment. HEN guidelines recommend assessing health-related quality of life (HRQoL) to evaluate the effect of the treatment. NutriQoL® is a specific questionnaire developed to assess HRQoL in patients receiving HEN and validated in Spanish population. An observational, descriptive, and prospective study was carried out in two Spanish hospitals to describe the evolution of HRQoL, nutritional and health status in patients receiving HEN in routine clinical practice. Fifty-seven patients participated in the study, of whom 36 were followed-up after their inclusion. Most of them were at risk or moderate malnutrition (61.1%) or showed severe malnutrition (27.8%) at baseline. Patients with HEN showed an overall good HRQoL with a mean basal NutriQoL® score of 69.4, which increased to 74.3 after 12 months of follow-up; fifteen patients showed a clinically significant difference (≥4 points) after three months. The proportion of at-risk or severely malnourished patients decreased at the end of the follow-up period and, according to the physicians, their health status improved. Additionally, physicians considered useful the HRQoL evaluation in clinical practice. In conclusion, HRQoL is probably related to nutritional status improvement and, thus, should be considered for nutritional evaluation in clinical practice.