A large body of research shows that social determinants of health have significant impact on the health of Canadians and Americans. Yet, very few studies have directly compared the extent to which social factors are associated with health in the two countries, in large part due to the historical lack of comparable cross-national data. This study examines differences in the effect of a wide-range of social determinants on self-rated health across the two populations using data explicitly designed to facilitate comparative health research-Joint Canada/United States Survey of Health. The results show that: 1) sociodemographic and socioeconomic factors have substantial effects on health in each country, though the size of the effects tends to differ-gender, nativity, and race are stronger predictors of health among Americans while the effects of age and marital status on health are much larger in Canada; the income gradient in health is steeper in Canada whereas the education gradient is steeper in the U.S.; 2) Socioeconomic status (SES) mediates or links sociodemographic variables with health in both countries-the observed associations between gender, race, age, and marital status and health are considerably weakened after adjusting for SES; 3) psychosocial, behavioural risk and health care access factors are very strong determinants of health in each country, however being severely/morbidly obese, a smoker, or having low life satisfaction has a stronger negative effect on the health of Americans, while being physically inactive or having unmet health care needs has a stronger effect among Canadians; and 4) risk and health care access factors together play a relatively minor role in linking social structural factors to health. Overall, the findings demonstrate the importance of social determinants of health in both countries, and that some determinants matter more in one country relative to the other.