OBJECTIVE: There is limited research on the impact of antidepressant treatment on family functioning. This study examines the impact of vortioxetine and agomelatine on family functioning using the Depression and Family Functioning Scale (DFFS). METHODS: The DFFS was included in REVIVE, a randomized, double-blind study of adults with major depressive disorder with inadequate response to antidepressant treatment who switched to vortioxetine or agomelatine. The prespecified DFFS analyses were performed using change from baseline to weeks 8 and 12, analyzed by mixed models for repeated measurements by treatment groups. Post hoc analyses compared DFFS scores for remitters and nonremitters. Patients were stratified into quartiles using DFFS scores, and scores on other clinical outcome assessments were compared. RESULTS: Sizeable improvements in DFFS scores were observed from baseline to week 8 (-10.8, -7.9 for vortioxetine and agomelatine, respectively), with further improvements at week 12 (-13.5, -11.0). Vortioxetine (n = 189) was superior to agomelatine (n = 187) by 2.9 DFFS points at week 8 (p < .01) and 2.5 points at week 12 (p < .05), and DFFS item-level improvements were also significantly greater for vortioxetine for 8 of 15 DFFS items at week 8 and 7 items at week 12. At week 8, remitters (n = 142) and nonremitters (n = 233) differed by 11 DFFS points; at week 12, remitters (n = 183) and nonremitters (n = 121) differed by almost 12 DFFS points. Patients stratified into baseline DFFS quartiles showed trends on clinical outcomes such that better family functioning was associated with better functional status and depressive symptoms. CONCLUSIONS: Vortioxetine was significantly superior to agomelatine in terms of family functioning and partner relationships, as well as social functioning, health status, and depression symptoms at weeks 8 and 12. Depressed patients with impaired family functioning showed worse overall functioning, health status, and depression symptoms, suggesting that more attention should be given to family functioning of depressed patients.