OBJECTIVES: Depression has a significant detrimental effect on HRQoL and functioning. The aim of this study was to assess HRQoL outcomes in randomized placebo-controlled studies of adult MDD patients receiving vortioxetine. METHODS: Effects on HRQoL and functioning were evaluated in adult MDD patients using the Short-Form 36 (SF-36), the Quality of Life Enjoyment and Satisfaction Scale-Short Form (Q-LES-Q-SF), the EuroQoL Five-Dimension (EQ-5D), the Health Status Questionnaire (HSQ-12) and the Sheehan Disability Scale (SDS). Furthermore, HRQoL and functioning were assessed in a short-term study in elderly MDD patients (≥65 years). A random effects meta-analysis was performed on the short-term vortioxetine studies (n=4 for SF-36 and n=7 for SDS). Values are presented as change from baseline versus placebo. RESULTS: Adult patients were treated with placebo (n=1316) or vortioxetine (n=2155). The meta-analysis (FAS, MMRM) showed a statistically significant difference to placebo in favour of vortioxetine in the SF-36 Mental Component Summary (MCS) score (5mg: 2.6, p=0.001, n=604; 20mg: 4.8, p<0.001, n=328) and 4 domain scores (vitality, social functioning, role-emotional, and mental health). Standardised effect sizes showed the clinical relevance of these results. Improvement was significantly different from placebo in the EQ-5D Health State score for vortioxetine 10mg (7.5 points, p<0.05, n=86) (FAS, MMRM) and the Q-LES-Q total score for vortioxetine 15mg (3.3 points, p<0.01, n=127) and 20mg (4.5 points, p<0.0001, n=134) (FAS, LOCF). Improvement in functioning, measured with the SDS, was in favour of vortioxetine 10mg (-1.7, p=0.004, n=269) and 20mg (-2.4, p=0.006, n=234) (FAS, MMRM). In the elderly study, improvement in the HSQ-12 for vortioxetine 5mg (n=136) was significantly different from placebo (n=128) for Health Perception (10.4, p<0.0001), Mental Health (7.9, p<0.001), and Energy (6.4, p<0.05) domains (FAS, MMRM). CONCLUSIONS: Vortioxetine showed significant and meaningful improvements in HRQoL and functioning versus placebo across several MDD trials and relevant outcome instruments.