Analyzing data from a telephone survey of rural and urban residents in South Carolina, this study attempts to understand how to better promote clinical trials (CTs) in rural areas. To explore why participation is lower among the rural population, we examine two groups of potential barriers: structural and procedural barriers (limited accessibility, lack of awareness, lack of health insurance) and cognitive and psychological barriers (lack of knowledge, misperceptions, distrust, fear). We then make a series of comparisons between rural and urban residents to see whether rural residents are significantly different from urban residents in terms of structural/procedural and cognitive/psychological barriers they are facing. Findings indicate that there are no significant differences between rural and urban residents in their willingness to participate in a CT. However, rural residents were more likely to perceive limited access to CT sites and lack of awareness of available trials. Rural residents also indicated greater lack of knowledge about CTs. Finally, we found that distrust and fear were important barriers in shaping one's willingness to participate in a CT. Implications of the findings are discussed in detail.