OBJECTIVETo evaluate the effect of relugolix combination therapy (relugolix CT; 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate) for up to 2 years in the SPIRIT long-term extension study on functioning and health-related quality of life (QoL), using the Endometriosis Health Profile (EHP)-30 questionnaire, and assess how changes in QoL domains correlated with improvements in dysmenorrhea as well as nonmenstrual pelvic pain (NMPP).DESIGNLong-term extension study of the SPIRIT phase 3 trials.SETTINGClinics and University Hospitals.PATIENT(S)Premenopausal women with moderate-to-severe endometriosis pain who previously completed the randomized SPIRIT trials were eligible to enroll in an 80-week long-term extension where all women received relugolix CT.INTERVENTION(S)Relugolix CT (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg).MAIN OUTCOME MEASURE(S)Least squares (LS) mean changes in the EHP-30 domain and total scores from baseline (pivotal) were analyzed using a mixed-effects model. Results up to 104 weeks are reported by a pivotal trial treatment group with a focus on the relugolix CT group (i.e., relugolix CT or placebo for 24 weeks, or delayed relugolix CT [relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT for 12 weeks]). In addition, the relationships between changes in dysmenorrhea and NMPP as well as changes in EHP-30 scores were assessed.RESULT(S)In the 277 women treated with relugolix CT, LS mean EHP-30 pain domain scores improved by 57.8% (LS mean change: -32.8; 95% CI: -35.5, -30.1), 66.4% (LS mean change: -37.7; 95% CI: -40.3, -35.0), and 72.2% (LS mean change: -41.3; 95% CI: -43.9, -38.7) at weeks 24, 52, and 104, respectively. The proportions of women with clinically meaningful improvement in the EHP-30 pain domain were 75.9%, 83.6%, and 88.6% at weeks 24, 52, and 104, respectively. Non-pain EHP-30 domain and total scores likewise improved. A positive correlation between changes in dysmenorrhea/NMPP and all EHP-30 domain scores was observed. Results were similar for the delayed relugolix CT and placebo → relugolix CT groups.CONCLUSION(S)Sustained reduction of endometriosis-associated pain with relugolix CT observed up to 104 weeks was accompanied by improvements in functioning and health-related QoL. These findings complement the results of the pivotal SPIRIT trials, which showed that relugolix combination therapy significantly reduced dysmenorrhea, NMPP, and dyspareunia vs. placebo in premenopausal women with endometriosis-associated pain.CLINICAL TRIAL REGISTRATION NUMBERRegistration/clinicaltrials.gov identifier: SPIRIT Extension Study (NCT03654274).