Background: Prostate cancer is the most common cancer in men in the United States. When comparing the incidence and mortality rates of prostate cancer in Appalachian Kentucky and general population in the United States, Appalachian Kentucky had lower incidence (113 per 100,000 rate vs. 137 per 100,000) but higher mortality rate (23.08% vs. 21.79%) from Surveillance Epidemiology and End Results (SEER) data in 2005-2014. The aim of our study is to further characterize the epidemiology and survival disparities of prostate cancer between Appalachian and non-Appalachian Kentucky. Methods: All stages of prostate cancer patients diagnosed between 2007-2011 were identified through Kentucky Cancer Registry (KCR). Baseline characteristics and survival outcome were compared between Appalachian Kentucky and non-Appalachian Kentucky. Kaplan-Meier plots and cox regression analyses were performed in this population-based study. Results: Out of 12871 patients studied, 3482 patients (26.8%) were Appalachian Kentucky whereas 8489 patients (73.2%) were non-Appalachian Kentucky. Caucasians were the most predominant in both groups. Most Appalachian Kentucky patients fell in the age group between 65-74. Appalachian Kentucky had high Gleason score, high prostate specific antigen (PSA), aggressive histologic grade, more distant disease, high comorbidity score, low high school education and high poverty rate compared to non-Appalachian Kentucky. There was a 5-year survival difference between Appalachian Kentucky and non-Appalachian Kentucky in unadjusted analysis (p < 0.0001). After adjusting with cox regression analysis, no survival difference was seen (p = 0.3866). However, statistical significance in survival was seen in high GLS, high PSA, distant stage, high charlson comorbidity score, and low high school education (p < 0.0001). Conclusions: Our study shows a significant difference in prostate cancer survival between Appalachian and non-Appalachian Kentucky. The difference was not related to geographic location, rather it was more related to high comorbidity score, high poverty rate, low education and less knowledge of health care. Additional research is needed to understand the health care in Appalachia.