In organ transplant recipients (OTRs), the risk of cutaneous squamous cell carcinoma (CSCC) is significantly raised. Actinic keratoses (AK) clearance was commonly used as a surrogate biomarker for CSCC prophylaxis. Although there was evidence that 5-fluorouracil (5-FU) at 5% might have been chemoprotective in immunocompetent individuals, OTR-CSCC chemoprevention with topical AK therapies has not been outlined in randomized controlled trials (RCT). For a study, the researchers sought to evaluate the feasibility, activity, and assessment outcomes of a future phase III RCT of topical CSCC chemoprevention in OTRs to construct a future phase III RCT. In a 15-month phase II open-label RCT, OTRs with 10 or more AKs in designated locations were randomized 1:1:1 to topical 5-FU, 5% -imiquimod (IMIQ) or sunscreen (SPF 30+). Proportions of eligible OTRs who were randomly assigned, completed therapy, and were willing to have retreated were among the feasibility outcomes. The researchers looked at AK activity (clearance, new AK formation), patient-centered outcomes (toxicity, HRQoL), and evaluation methods (clinical versus photographic). A total of 40 OTRs with a total of 903 AKs were enlisted. All of the feasibility goals were met (67% of eligible OTRs randomized; 88% completed treatment; 95% willing to be re-treated). 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs in AK activity studies. In exploratory investigations, 5-FU outperformed IMIQ in terms of AK clearance and prevention. Although the toxicity of 5-FU was higher, the HRQoL outcomes were identical. Topical AK treatments for CSCC chemoprevention in OTRs were viable, and AK activity results supported additional research into 5-FU-based treatments in phase III research in the future.