OBJECTIVES: To evaluate the effects of lisdexamfetamine dimesylate (LDX) on changes in health-related quality of life (HRQoL) in individuals with protocol-defined moderate to severe binge eating disorder (BED). METHODS: In 2 identically designed 12-week, double-blind, placebo-controlled trials, adults with protocol-defined moderate to severe binge eating (BE) who met DSM-IV-TR BED criteria were randomized (study 1, N=383; study 2, N=390) to placebo or LDX (50 or 70 mg). HRQoL was assessed at baseline and treatment weeks 4, 6, 8, 10, and 12/early termination using the EuroQoL 5-Dimension 5-Level Questionnaire (EQ-5D-5L; a prespecified secondary endpoint). For this post hoc analysis, participant EQ-5D-5L profiles were converted to utility index scores (range: –0.109 [worst state] to 1 [best state]) and pooled across studies. Unadjusted and adjusted random effect tobit regressions were conducted to examine the longitudinal relationship between LDX treatment and HRQoL. RESULTS: Mean ± SD EQ-5D-5L index scores in the pooled treatment groups were 0.877±0.105 for placebo (n=358 observations) and 0.882±0.118 for LDX (n=364 observations) at baseline and 0.909±0.115 for placebo (n=296 observations) and 0.933±0.102 for LDX (n=302 observations) at week 12. Mean (95% CI) improvement/week in EQ-5D-5L index scores without adjustment was statistically significant for placebo (0.0059 [0.005, 0.007]; P<0.001) and for LDX relative to placebo (0.0032 [0.001, 0.005]; P=0.001). Treatment effects on HRQoL were no longer significant after adjusting for BE episodes/week, functionality, and impairment in work and daily activities (placebo, –0.0001 [–0.002, 0.002], P=0.9; LDX relative to placebo, 0.0006 [–0.002, 0.003], P=0.6) or after adjusting for BE days/week, functionality, and impairment in work and daily activities (placebo, –0.0008 [–0.003, 0.002], P=0.5; LDX relative to placebo, 0.0002 [–0.002, 0.003], P=0.9). CONCLUSIONS: The positive effect of LDX on HRQoL/patient utlility is indirect and mediated in part by LDX effects on BE frequency and disability/functioning.