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Background: Self-reported moderate to vigorous physical activity (MVPA) has been associated with better health-related quality of life (HRQoL), however research on quantitative MVPA in relation to HRQoL has been limited. In addition, the association of PA with physical and mental health components of HRQoL has not been examined.Hypothesis: Higher accelerometer-measured MVPA will be associated with better mental and physical HRQoL.Methods: Cross-sectional data from 12,179 adults ages 18-74 in 2008-11, who participated in HCHS/SOL and had complete data on key study variables. MVPA (minutes/week), measured by accelerometer, was grouped into 4 levels: inactive, low, moderate, and high. HRQoL was assessed using the Short-Form 12 (SF-12) questionnaire; the SF-12 mental and physical component summary (MCS; PCS) scores were computed (standardized to general US population norms with mean of 50 and standard deviation of 10; higher scores indicate better HRQoL). Multivariable linear regression models were used to derive adjusted means with 95% confidence intervals (CI) and to assess linear trends. All models were adjusted for covariates. The analyses were weighted for the study design and non-response.Results: PCS adjusted mean scores ranged from 46.8 (CI: 44.9, 48.6) among inactive persons to 51.3 (CI: 50.8, 51.8) among those with high levels of MVPA (ptrend <0.001). No significant differences in MCS scores were observed across MVPA levels (p = 0.64).Conclusion: MVPA was positively associated with better self-perceived physical health-related quality of life. Our findings align with studies examining self-reported MVPA and HRQoL. Future prospective studies should evaluate whether increasing MVPA can lead to improvements in HRQoL among the US Hispanic/Latino population.