Background: Adjuvant tx of resected stage III BRAF-mutant melanoma with D + T significantly reduced risk of recurrence vs placebo (pbo). In the COMBI-AD study, 1-y tx with D + T resulted in improvements in relapse-free survival, distant metastasis–free survival, freedom from relapse, and overall survival. The effect of D + T on HRQOL in the adjuvant setting is reported here. Methods: COMBI-AD (NCT01682083) was a randomized, double-blind, phase 3 study evaluating pts with resected stage III BRAF V600E/K–mutant melanoma. Pts were randomized 1:1 to receive D 150 mg twice daily plus T 2 mg once daily or matching pbo for 12 mo. HRQOL assessment using the EuroQol-5D (EQ-5D-3L) questionnaire and visual analogue scale (VAS) was an exploratory endpoint. A mixed-model, repeated-measures analysis was used to assess differences in mean scores. Results: A total of 870 pts were randomized (D + T, n = 438; pbo, n = 432). Although pts available for assessment declined during study primarily due to consent withdrawal, missed scheduled visits, and deaths, completion rates among available pts were high (98% at baseline [BL], ≥ 90% throughout the 12-mo tx period, and ≥ 75% at assessments after 12 mo). Pts in both arms had similar BL VAS values (D + T, 79.0; Pbo, 80.4 [0-100 scale]). During tx (3- to 12-mo assessments), VAS scores remained similar to BL, with no clinically meaningful differences observed between arms (adjusted mean change from BL at 12 mo: D + T, 0.14; pbo, −0.02). In the D + T arm, no clinically meaningful or statistically significant difference in VAS was reported between pts who did and did not experience pyrexia (P> .1). During follow-up (15-48 mo), VAS scores were similar between arms, with no significant or clinically meaningful differences reported. At relapse, a statistically significant reduction in VAS score was observed in both arms (mean difference [pre- vs postrecurrence], D + T, −6.02, P = .003; pbo, −6.84, P< .001). Conclusions: In the absence of disease-related symptoms in the adjuvant setting, these results demonstrate that D + T do not negatively impact HRQOL during tx or in long-term follow-up and further emphasize the importance to pt HRQOL of preventing relapse. Clinical trial information: NCT01682083