Background: In the phase 3 study (SANET-ep, NCT02588170), surufatinib significantly prolonged progression free survival compared with placebo in patients with progressive, well-differentiated advanced extrapancreatic neuroendocrine tumors (epNETs) (ESMO 2019 Abs. LBA76). Here, we report the results of health-related quality-of-life (HRQoL) from this study. Methods: Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo, 300 mg, orally, once daily, until disease progression or intolerable adverse events. Patient-reported outcome questionnaires, including the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-G.I.NET-21, were collected at baseline, Day 15 of the first cycle (28 Days/cycle), and Day 1 of every cycle thereafter and at discontinuation. Time until definitive deterioration (TUDD) was defined as time from randomization to deterioration of 10 points in domain score compared with baseline score (without subsequent observations of deterioration of less than 10 point or any improvement as compared to baseline score), or death due to any cause. TUDD and mean change from baseline based on a longitudinal repeated measures analysis of each domain were analyzed retrospectively. Significance testing was at two-sided 0.05 without adjustment for multiplicity. Results: Of 198 pts randomized (surufatinib n = 129; placebo n = 69), 197 (99.5%) patients completed HRQoL questionnaires at baseline. The questionnaire compliance rate was >90% for most on-treatment assessments. The TUDD was significantly longer in the surufatinib arm versus the placebo arm in the dyspnea domain (hazard ratio [HR] 0.52, p = 0.0103) and social function scale (HR 0.58, p = 0.0222), while the TUDD of diarrhea was significantly shorter in the surufatinib arm compared to placebo (HR 2.68, p = 0.0074). There was no significant difference of TUDD in the remaining domains of QLQ-C30 and G.I.NET-21. There was also no significant difference of the mean change of scores from baseline by repeated measures in the domains between the two arms except diarrhea (increase of 14.0 points [95% CI 9.6, 18.4] in the surufatinib arm versus 2.1 points [95% CI -4.1, 8.4] in the placebo arm, p = 0.0007). Conclusions: Treatment with surufatinib resulted in superior efficacy, acceptable toxicity, while generally maintaining HRQoL, which support surufatinib as a treatment option in this patient population that was previously treated with available therapies for epNETs. Clinical trial information: NCT02588170.