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Past studies have suggested a relationship between opioid overdoses and economic trends that have worsened the quality of jobs for the less educated in particular, though the research to date has been largely quantitative. Drawing from thirty-two in-depth interviews and observations of non-college-educated men and women in central Virginia with recent histories of opioid use and joblessness, we examine mechanisms by which working-class status contributes to risky health behaviors. What we call precarity chains—overlapping forms of economic, social, physiological, and legal precarity—create a state of vulnerability where disadvantages in one area bleed over into another, putting individuals at continual risk of falling into substance use. Frayed family safety nets mean that misfortune or lapses in judgment spiral out into larger crises, often at decisive pivot points. Meanwhile, a culture and economy built in part on pharmaceutical innovation contributes to various forms of instability, which become visible in the interweaving and bridging use of substances within this group.