Background: The U.S. is in the throes of two concurrent epidemics: too many people die from opioid-related fatalities, but too many people continue to suffer in pain. In certain regions this dilemma is particularly pronounced. For example, Southwest (SW) Virginia is a rural area with disproportionately high cancer mortality rates and high rates of opioid fatalities. Little is known about how to most effectively and safely manage pain in a region where there exists both a high cancer burden and significant opioid misuse. Purpose: Describe prescription opioid medication (POM) use for patients with cancer in SW Virginia and potential harms. Methods: This is a longitudinal, exploratory, secondary data analysis using the Virginia All Payers Claims Database (APCD), which includes paid medical and pharmacy claims data on 4 million individuals in the Commonwealth of Virginia. Patients with a diagnosis of cancer who lived in far, rural SW Virginia between 2011–2015 were included. Outpatient prescription data were linked to hospitalization admission claims data to explore potential opioid-related harms. Analysis was conducted at the patient, prescription and prescriber level (SAS 9.4, STATA 13.1) to identify predictors of POM use and opioid-related substance use admissions. Results: Within the APCD, POMs represent 7.23% of all medications prescribed for patients with cancer, with hydrocodone- and oxycodone-combinations, oxycodone, fentanyl transdermal patch and morphine sulfate being the most common. Over 50% of patients were prescribed a POM at least once during the study period. Multi-level logistic regressions suggest age, payer source, cancer type, gender, prescriber type and specialty were all significant (p < .001) predictors of being prescribed POMs. Preliminary analyses of hospitalized cancer patients found no association between POM use and opioid-related substance use hospitalization. Conclusions: A clearer view of geographic patterns and predictors of both POM use and potential harms can inform targeted clinical interventions and policy initiatives that achieve a balanced approach to POMs – ensuring access for patients in need, while reducing risk.