OBJECTIVES: Mortality rates generally decline during economic recessions in high-income countries, however gaps remain in our understanding of the underlying mechanisms. This study estimates the impacts of increases in unemployment rates on both all-cause and cause-specific mortality across U.S. metropolitan regions during the Great Recession. METHODS: We estimate the effects of economic conditions during the recent and severe recessionary period on mortality, including differences by age and gender subgroups, using fixed effects regression models. We identify a plausibly causal effect by isolating the impacts of within-metropolitan area changes in unemployment rates and controlling for common temporal trends. We aggregated vital statistics, population, and unemployment data at the area-month-year-age-gender-race level, yielding 527,040 observations across 366 metropolitan areas, 2005-2010. RESULTS: We estimate that a one percentage point increase in the metropolitan area unemployment rate was associated with a decrease in all-cause mortality of 3.95 deaths per 100,000 person years (95%CI -6.80 to -1.10), or 0.5%. Estimated reductions in cardiovascular disease mortality contributed 60% of the overall effect and were more pronounced among women. Motor vehicle accident mortality declined with unemployment increases, especially for men and those under age 65, as did legal intervention and homicide mortality, particularly for men and adults ages 25-64. We find suggestive evidence that increases in metropolitan area unemployment increased accidental drug poisoning deaths for both men and women ages 25-64. CONCLUSIONS: Our finding that all-cause mortality decreased during the Great Recession is consistent with previous studies. Some categories of cause-specific mortality, notably cardiovascular disease, also follow this pattern, and are more pronounced for certain gender and age groups. Our study also suggests that the recent recession contributed to the growth in deaths from overdoses of prescription drugs in working-age adults in metropolitan areas. Additional research investigating the mechanisms underlying the health consequences of macroeconomic conditions is warranted.