Clinical trials are needed to inform evidence-based smoking cessation approaches in rural and Appalachian women, but trial enrollment in these groups is sparse. Little is known about factors associated with enrollment of Appalachian women in tobacco dependence treatment randomized clinical trials (RCT). We report a comparison of Appalachian women enrolling in a tobacco dependence treatment RCT to those declining and identify correlates to enrollment. Smokers identified during a cervical health-related survey among Ohio Appalachian women were invited to enroll in a tobacco dependence treatment RCT incorporating behavioral counseling and nicotine replacement. Women who agreed to enroll were compared to women who declined in terms of sociodemographic, health- and smoking-related measures. The mean age of women sampled was 35.1 years. Women reported daily consumption of 1-10 (39%), 11-20 (46%), or >20 (16%) cigarettes. In a multivariable logistic regression model adjusting for age and nicotine dependence, pros of smoking most outweighing cons (odds ratio [OR] = 0.11, 95% confidence intervals [CI] = 0.03, 0.39), ≥3 prior quit attempts versus 1 attempt (OR = 0.18, 95% CI = 0.06, 0.59), and not having health insurance (OR = 0.29, 95% CI = 0.12, 0.77) were associated with decreased odds of RCT enrollment. Rural Appalachian women who enrolled in a tobacco dependence treatment RCT differed significantly in motivational and cognitive attitudes toward smoking, insurance status, and number of prior quit attempts, as compared to those who did not enroll. Techniques that foster motivation to quit smoking as a means of boosting RCT enrollment are discussed.