The recent opioid epidemic in the rural Appalachian region of the United States has fueled an exponential increase in hepatitis C virus (HCV) infection among People Who Inject Drugs (PWID). Needle exchange programs (NEP), which provide clean needles in exchange for used needles, can reduce the incidence of HCV among PWIDs. However, the empirical evidence examining NEP effectiveness in the prevention of HCV in this population is mixed, only describes studies conducted in urban areas, and does not address the unique challenges associated with implementing NEPs in rural areas. Furthermore, no studies have examined barriers to using clean needles obtained from NEPs in rural settings. Therefore, there is a critical need to understand the unique context and programmatic challenges of rural NEPs to design and implement successful programs to reduce HCV transmission in this underserved population. The objective of this dissertation was to improve empirical evidence related to NEP efficacy, examine programmatic challenges encountered by rural NEPs, and identify clean needle use barriers unique to rural areas. The rationale underlying this research is that improved understanding of operational and clean needle use barriers will promote successful implementation of NEPs in rural areas. In the first study, a systematic review with meta-analysis was conducted to update the empirical evidence related to NEP prevention of HCV in PWIDs. Findings from this study revealed that the overall impact of NEPs on HCV prevention remains unclear and is complicated by significant heterogeneity between studies. Furthermore, no rural studies were identified in the review. Standardization of population characteristics, intervention components, empirical comparisons, and outcome assessments is suggested to reduce heterogeneity and clarify the empirical contribution of NEPs to HCV prevention. In the second study, a qualitative case study design was employed to examine barriers and facilitators to NEP implementation, ongoing operations, and future sustainability. Structured interviews with program directors, law enforcement leaders and personnel, and NEP attendees revealed common barriers and facilitators to program operations. Findings from this study indicated that despite broad community support, growing volumes, funding shortages, and the federal government's prohibition on the use of funds to purchase needles threatened program operations. Furthermore, paraphernalia laws created a legal conundrum in the form of criminal sanctions for the possession of needles, which may inadvertently promote needle sharing and disease transmission. In the third study, a mixed methods survey of PWIDs attending two rural, Appalachian programs regarding barriers to using clean needles obtained from the exchange for every injection was employed. Findings from this study revealed that fear of arrest and problems with obtaining clean needles from pharmacies were the most commonly endorsed barriers to clean needle use. The results of this dissertation suggest that ...