Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with ¹⁷⁷Lu-DOTATATE (¹⁷⁷Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the ¹⁷⁷Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on ¹⁷⁷Lu arm vs. 15% on Oct, and worsened in 18% of patients on ¹⁷⁷Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on ¹⁷⁷Lu vs. 23% on Oct, and worsened in 19% of patients on ¹⁷⁷Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with ¹⁷⁷Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with ¹⁷⁷Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of ¹⁷⁷Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239