Recent research has found, in some groups of Americans, dramatic increases in deaths due to drug overdose and suicide and an overall stagnation of trends toward increased longevity. This study examines the link between mortality of older working age (45 to 64) adults and local economic downturns in the U.S. to evaluate the role of economic shifts in various causes of death and their related mortality trends. Specifically, we estimate regression models to test the hypotheses that the longevity effects of poor economic prospects are reflected through (1) increased suicide, drug overdose, and other “deaths of despair” and (2) other causes of death linked to exposure to economic and social stress such as heart and cerebrovascular disease. To avoid the problem of endogeneity of local economic conditions to mortality conditions, we measure the local economic shock of lost employment with predicted employment based on baseline industrial composition and national trends in employment by industry. We find evidence consistent with prior research that among non-Hispanic white adults, midlife mortality has increased since 1990, particularly among those with low educational attainment. We also find that “deaths of despair” are important contributors to that trend. However, we find that while distress in local, area economies does predict increased mortality for chronic disease, it predicts decreased mortality from suicides, opioids, and other substance abuse. This finding suggests caution in the application of the construct of despair in explaining recent mortality patterns.