Objectives: To analyze the effect of weight on psychological and functional outcomes in multiple sclerosis (MS) patients, including self-perception, depression, functional level, fatigue, and self-rated health status. Methods: One hundred and one (n = 101) patients with MS participated in this cross-sectional study. Outcomes were scores in the Beck Depression Inventory, NEO Five-Factor Inventory (NEOFFI), Functional Assessment of Multiple Sclerosis (FAMS), Fatigue Impact Scale, and Quality Short-Form Health Survey 36 (SF-36). Patients were classified as normal weight (18.5 < BMI < 24.9 kg/m(2)) or overweight (25.0 > BMI > 29.9 kg/m(2)). One-way analysis of covariance was conducted with gender, age, and years with disease as covariates. Results: Depression levels were significantly higher in overweight versus normal-weight MS patients (F = 6.381; P = 0.013). NEOFFI scores were significantly higher in overweight versus normal-weight MS patients for extraversion (F = 6.331; P = 0.014), conscientiousness (F = 4.794; P = 0.034), and neuroticism (F = 5.422; P = 0.022) but not for openness (F = 2.174; P = 0.109) or agreeableness (F = 0.047; P = 0.829). The two groups did not significantly differ in fatigue (P > 00.5). Scores in general (F = 4.708; P = 0.032) and mental health (F = 4.583; P = 0.035) SF-36 domains were significantly lower in overweight versus normal-weight patients. Scores for FAMS domains of emotional well-being (F = 8.050; P = 0.006), general contentment (F = 7.967; P = 0.006), and family/social well-being (F = 7.662; P = 0.007) were significantly lower in overweight versus normal-weight patients. Conclusions: Overweight MS patients evidenced higher depression levels, lower functional capacity, and worse self-rated health status in comparison to normal-weight MS patients. These results suggest that weight control programs should be incorporated into the management of patients with MS.