Background: No previous research has examined the association between metabolic syndrome (MetSyn) and health-related quality of life (HRQoL) using standard criteria for defining MetSyn. We hypothesized that MetSyn would be associated with lower HRQoL on measures of physical and mental health. Methods and Procedures: Participants were 361 individuals in two randomized weight loss trials. MetSyn was defined by the National Cholesterol Education Panel criteria. The Medical Outcomes Study, Short Form-36 (SF-36) was used to assess HRQoL. Differences in HRQoL and in clinical and psychosocial characteristics were compared among participants with and without MetSyn. Multiple regression was used to determine predictors of HRQoL. Results: MetSyn was associated with lower scores on the physical function and general health subscales of the SF-36 and on the physical component summary (PCS) score. This association remained after controlling for age or depression but was eliminated by controlling for BMI. MetSyn was not associated with lower mental quality of life, a higher depression score, tobacco or alcohol use, or a higher rate of psychosocial stressors. Discussion: Individuals with MetSyn reported lower HRQoL. This appeared to be an effect of increased weight, rather than a unique effect of MetSyn. Larger studies are needed to assess whether MetSyn may have an independent effect on HRQoL