Introduction: Home parenteral nutrition (HPN) is a rare but challenging therapy and care for patients with mostly severe underlying diseases. We aimed to investigate patient-reported health-related quality of life (QOL) of patients receiving HPN and its development over time in particular. Methods: We assessed QOL of HPN patients in a prospective multicenter observational study (SWISSHPN II study). We designed a questionnaire to record symptoms and negative impacts of HPN and completed the validated Optum® SF-36v2® Health Survey with the patients. Results: 70 patients (50% women) on HPN were included. PN commonly affected feelings of dependency (n = 49, 70%), traveling/leaving home (n = 37, 53%), attending cultural and social events (n = 25, 36%), and sleep (n = 22, 31%). Most frequently reported symptoms were diarrhea (n = 30, 43%), polyuria (n = 28, 40%), nausea/emesis (n = 27, 39%), dysgeusia (n = 23, 33%), and cramps (n = 20, 29%). At baseline, mean (SD) SF-36v2® physical and mental health component summary scores (PCS and MCS) were 45 (20) and 57 (19), respectively, and there was a trend towards improvement in PCS over the study period while MCS remained stable. Satisfaction with health care professionals involved in HPN care was high. Conclusion: QOL is a crucial and decisive aspect of HPN patient care. Symptoms related to the underlying disease and PN are frequent. Impaired social life and an ambivalent attitude towards the life-saving therapy are major concerns for these patients and should be addressed in their care.