OBJECTIVES: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI) in clinical development for the treatment of major depressive disorder (MDD). Primary and post hoc analyses were conducted on data from a positive Phase III trial (NCT00969709) to evaluate the functional health and well being of patients with MDD treated with sustained released (SR) levomilnacipran.  METHODS: A double-blind, multicenter, parallel-group, placebo-controlled, fixed-dose study in patients aged 18-65 years who met DSM-IV-TR criteria for MDD and Montgomery-Asberg Depression Rating Scale-Clinician Rated (MADRS-CR) score ≥30. Study comprised a 1-week single-blind, placebo lead-in, 8-week double-blind treatment, and 2-week double-blind down-taper. Patients were randomized to placebo (n=175) or once-daily levomilnacipran (n=529) 40 mg, 80 mg, or 120 mg (titrated-up from an initial dose of 20 mg). Functional health and well being were measured using change from baseline to Week 8 on the SF-36v2 acute (1-week recall) health survey. Individual health dimensions, and physical (PCS) and mental (MCS) component summary scores were compared for levomilnacipran and placebo (ITT population) using an ANCOVA model.  RESULTS: Patients in both groups had deficits in mental-health (baseline MCS scores: (placebo, 17.2±9.2; levomilnacipran, 18.2±8.5); baseline PCS scores (PBO: 52.6±11.1; LVM: 51.1±11.1) were slightly higher than the population norm. Following 8 weeks of treatment, levomilnacipran patients versus placebo demonstrated significantly greater improvement in MCS (LSMD=4.4±1.36; P=.0013) and on several individual dimensions (General Health [2.3±0.69; P=.0007], Vitality [2.4±1.05, P=.0228], Social Functioning [3.1±1.17; P=.0086], Role Emotional [3.1±1.20; P=.0097], Mental Health [4.3±1.16; P=.0003]. Nonsignificant PCS [-0.2±0.74; P=.8386] and other dimension score changes were noted. CONCLUSIONS: Levomilnacipran patients experienced statistically significant and clinically meaningful improvements in functional health and well being as measured by the SF-36 MCS and associated individual dimensions. Nonsignificant changes were noted for the PCS and associated individual dimensions. Supported by funding from Forest Laboratories, Inc.