Measures of quality of life (QoL) have been found to be predictors of mortality and morbidity; however, there is still limited understanding of the multifaceted nature of these measures and of potential correlates. Using two large populations from the UK and US, we aimed to evaluate and compare measured levels of QoL and the key factors correlated with these levels. Participants were 6,472 white subjects (1,829 women) from the Whitehall II Study (mean age 55.8 years) and 3,684 white subjects (1,903 women) from the Western New York Health Study (mean age 58.7 years). QoL was assessed in both using the physical and mental health component summaries of the short form-36 questionnaire (SF-36). Analysis of covariance was used to compare gender-specific mean scores for the two populations across several potential correlates (including socio-demographic, lifestyle and co-morbidity factors). Levels of reported physical QoL tended to be higher in the UK population (51.2 vs. 48.6) while mental QoL was higher in the US group (53.1 vs. 51.1). Age, sleep duration and depressive symptoms were the main factors correlated with both physical and mental QoL in both samples. Increasing age was associated with poorer physical health but higher mental health scores in both populations (P<0.001). Sleep duration below 6 or above 8 h was associated with lower levels of QoL. Depressive symptoms were strongly associated with poorer mental health scores (P<0.001) while higher BMI, lower physical activity levels and presence of cardiovascular disease were associated with poorer physical health in both samples and gender (P<0.05). There were consistent findings for correlates of QoL in this cross-cultural comparison of two populations from the UK and US. Strongest associations were between lifestyle and co-morbidity factors and the physical health component of the SF-36 rather than the mental health component. This is a novel finding which warrants further consideration.