Pre-exposure prophylaxis (PrEP), a biomedical tool to prevent the acquisition of HIV, reduces the risk of HIV in high-risk individuals by more than 90%. An online questionnaire was fielded from March 2017 to May 2017 to a random sample of licensed advanced practice nurses (APNs) from the U.S. state of Indiana. Discriminant function analysis was performed to reveal willingness to prescribe PrEP. Two discriminant functions were identified: Sexual Risk Assessment (r = .686), PrEP Barriers (r = .587), Evidence-Based Practice Implementation (r = .545), Community Awareness (r = .446), Perceived Risk (r = .356), and Organizational Climate (r = .346) were loaded on the first function, whereas PrEP Skills (r = .837) was loaded on the second function. The results suggest APN's willingness to learn and knowledge about PrEP-influenced implementation. Findings demonstrated that readiness to prescribe PrEP by APNs in Indiana could be predicted with a high level of certainty using identified variables.