The United States is in the midst of a fatal drug epidemic. This study uses data from the Multiple Cause of Death Files to examine the extent to which increases in county-level drug mortality rates from 1999-2015 are due to “deaths of despair”, measured here by deterioration in mediumrun economic conditions. Multiple proxy methods are used to address the issue that no single variable adequately captures all aspects of the economy. Robustness tests are included, as well as examination of the sensitivity of the main results to controlling for selection on unobservables. The primary finding is that counties experiencing relative economic decline did experience higher growth in drug mortality than those with more robust growth, but the relationship is weak and mostly explained by confounding factors. In the preferred estimates, changes in economic conditions account for just one-ninth of the variation in growth of drug mortality rates, with a slightly greater portion of heroin-involved overdose death rates explained but virtually none of the increase opioid analgesic mortality. The contribution of economic factors is even less when accounting for selection on unobservables. These results suggest that the “deaths of despair” framing, while provocative, fails to explain the main sources of the fatal drug epidemic and that efforts to improve economic conditions in distressed locations, while desirable for other reasons, are not likely to yield significant reductions in drug mortality.