Although all-cause mortality rates have fallen in many countries in the last 40 years, the well-off and city dwellers have experienced the greatest gains. In this paper, we report on socio-economic and regional variations in premature mortality in Ontario. Premature mortality rates were highest in areas with the greatest degrees of social deprivation. While premature mortality continued to fall in the least deprived group, they flattened in the other groups and rose between 2000–2007 and 2008–2015 in the most deprived group. There were substantial variations in premature mortality rates across the Local Health Integration Networks, with the greatest disadvantage being seen in the southeast, northwest and northeast regions of Ontario. These data present a major challenge to policy makers. Health, social and economic policies need to be directed toward narrowing the gaps we have identified here. We have excellent metrics with which to measure their success.