OBJECTIVES: Few studies have measured the impact of antidepressant treatment on family functioning. The effect of vortioxetine and agomelatine on different domains of family functioning was measured using the Depression and Family Functioning Scale (DFFS), comprising 15 items, each rated from 0-4.  METHODS: The DFFS was assessed in REVIVE, a randomized, double-blind study of adults with an inadequate response to antidepressant treatment for the current depressive episode switched to vortioxetine or agomelatine (NCT01488071). Pre-specified analyses of patients with baseline and follow-up DFFS assessments were performed using change from baseline to weeks 8 and 12, analyzed by mixed models for repeated measurements (MMRM). Descriptive statistics characterizing depressive symptoms (Montgomery-Åsberg Depression Rating Scale; MADRS), functioning (Sheehan Disability Scale; SDS), and quality of life (QoL; EQ-5D) were stratified according to DFFS total score quartiles at baseline.  RESULTS: The DFFS total score was ~29 at baseline. Vortioxetine (n=189) was superior to agomelatine (n=187) by 2.9 (95% CI [-4.7 to -1.1]) points at week 8 (p<0.01) and at week 12 by 2.5 (95% CI [-4.5 to -0.5; p<0.05]) points. Improvements in the DFFS total score and items were observed from baseline to week 8 (-10.8±0.7 (vortioxetine) and -7.9±0.7 (agomelatine), with further improvement at week 12 (-13.5±0.8 (vortioxetine) and -11.0±0.8 (agomelatine)). At baseline, the level of family functioning was associated with functional and QoL impairment and, to a lesser extent, depressive symptoms (SDS total=14.66, 19.31, 20.25, 21.68; EQ-5D=0.68, 0.58, 0.53, 0.44; MADRS=26.97, 28.83, 29.39, 29.67 in the first, second, third, and fourth DFFS quartiles, respectively; p<0.01).   CONCLUSIONS: Vortioxetine was significantly superior to agomelatine in terms of change in DFFS total score at weeks 8 and 12. Depressed patients with impaired family functioning showed worse overall functioning and QoL, suggesting that attention should be given to family functioning of depressed patients.