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Background Using a new needle for every injection can reduce the spread of infectious disease among people who inject drugs (PWID). No previous study has examined new needle use barriers among PWIDs residing in the rural Appalachian part of the United States, an area currently in the midst of a heroin epidemic. Objective Therefore, our primary aim was to explore self-reported barriers to using a new needle by PWID attending a needle exchange program (NEP). Methods We conducted a cross-sectional survey of PWID attending two NEPs in rural West Virginia located in the heart of Central Appalachia. A convenience sample of PWID ( n  = 100) completed the Barriers to Using New Needles Questionnaire. Results The median number of barriers reported was 5 (range 0–19). Fear of arrest by police (72% of PWID “agreed” or “strongly agreed”) and difficulty with purchasing needles from a pharmacy (64% “agreed” or “strongly agreed”) were the most frequently cited barriers. Conclusions/Importance Congruent with previous findings from urban locations, in rural West Virginia, the ability of PWID to use a new needle obtained from a needle exchange for every injection may be compromised by fear of arrest. In addition, pharmacy sales of new needles to PWID may be blunted by an absence of explicit laws mandating nonprescription sales. Future studies should explore interventions that align the public health goals of NEPs with the occupational safety of law enforcement and health outreach goals of pharmacists.