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There has been a steep rise in overdoses and mortality among people who use opioids or who inject drugs (PWUD), including in North America, the United Kingdom, and parts of Eastern Europe, with some of the sharpest increases amassing in rural communities. Currently, the literature lacks a comparative focus on the views and experiences of rural PWUD and professionals who regularly work and interface with them, in terms of their understandings of the rural drug use initiation/relapse trajectory. Considering a renewed sociology of emotions and empathy and the constructs of direct experience (e.g., of personal drug use) versus role‐playing (e.g., envisioning oneself in another's position), we used a modified constant comparison method to analyze interviews conducted with PWUD and professional stakeholders in rural southern Illinois, an opioid overdose hotspot. Findings suggest that rural opioid use is adopted in service of an intricate interplay of sensory, relational, somatic, and psychosocial benefits, with a sharp divergence between PWUD, who express considerable agency in their drug use behaviors, and professionals, who fail to successful role‐play in emphasizing PWUD's limited willpower and "deviant" sociocultural predilection. These dynamics illuminate challenges to advancing nuanced, culturally humble programming to advance public health goals related to the opioid and drug injection epidemic. [ABSTRACT FROM AUTHOR]