Cancer mortality is higher in counties with high levels of (current) poverty, but less is known about associations with persistent poverty. Persistent poverty counties (with ≥20% of residents in poverty since 1980) face social, structural, and behavioral challenges that may make their residents more vulnerable to cancer. We calculated 2007 to 2011 county-level, age-adjusted, and overall and type-specific cancer mortality rates (deaths/100,000 people/year) by persistent poverty classifications, which we contrasted with mortality in counties experiencing current poverty (≥20% of residents in poverty according to 2007-2011 American Community Survey). We used two-sample t tests and multivariate linear regression to assess mortality by persistent poverty, and compared mortality rates across current and persistent poverty levels. Overall cancer mortality was 179.3 [standard error (SE) = 0.55] deaths/100,000 people/year in nonpersistent poverty counties and 201.3 (SE = 1.80) in persistent poverty counties (12.3% higher, P < 0.0001). In multivariate analysis, cancer mortality was higher in persistent poverty versus nonpersistent poverty counties for overall cancer mortality as well as for several type-specific mortality rates: lung and bronchus, colorectal, stomach, and liver and intrahepatic bile duct (all P < 0.05). Among counties experiencing current poverty, those counties that were also experiencing persistent poverty had elevated mortality rates for all cancer types as well as lung and bronchus, colorectal, breast, stomach, and liver and intrahepatic bile duct (all P < 0.05). Cancer mortality was higher in persistent poverty counties than other counties, including those experiencing current poverty. Etiologic research and interventions, including policies, are needed to address multilevel determinants of cancer disparities in persistent poverty counties. ©2020 American Association for Cancer Research.