Key PointsQuestionIs the interaction between income inequality and social mobility associated with an increased risk of deaths of despair (deaths from suicide, drug overdose, and alcoholic liver disease) among the working-age population in the US?FindingsIn this cross-sectional study, higher income inequality and lower social mobility were associated with a higher burden of deaths of despair for Black, Hispanic, and White populations. In addition, the joint exposure of unequal income distribution and lack of social mobility was associated with additional risks of deaths of despair on both the additive and multiplicative scales.MeaningThe findings of this study suggest that policy responses to the epidemic of deaths of despair must address the underlying social and economic conditions associated with these deaths.