Abstract Background Keratinocyte carcinomas (KCs), comprising basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common skin cancers worldwide. Actinic keratoses (AKs) are precursors to SCCs and markers of cumulative ultraviolet damage. Chemoprevention has been explored in high-risk or immunosuppressed cohorts, however their value in immunocompetent adults remains unclear. Methods Following Cochrane guidelines, we searched Medline, Embase and Cochrane CENTRAL (January 1985 – August 2025). Eligible studies were randomised controlled trials (RCTs) of immunocompetent adults evaluating topical or oral agents versus placebo/control and reporting KC or AK incidence. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Results Eleven RCTs (n=7,355) were included. Daily sunscreen significantly reduced the incidence of AKs by 24-51% across three trials (p0.05), and SCCs (0.61 95% CI 0.46-0.81) versus placebo. Nicotinamide reduced SCCs by 30% and AKs by 13-35% across two trials (p0.05). Topical 5-fluouracil (5-FU) reduced superficial BCCs by 59% (p=0.005). Oral retinoids yielded inconsistent results and were associated with frequent adverse effects. Oral difluoromethylornithine (DFMO) reduced BCC incidence by 30% in one trial (p=0.03) but also caused persistent hearing loss in 19%. Conclusions This is the first systematic review focused exclusively on chemoprevention in immunocompetent adults. Sunscreen remains the foundation of skin cancer prevention. Nicotinamide and 5-FU show promise, whereas retinoids and DFMO lack sufficient efficacy or safety for routine use. Future trials should evaluate long-term nicotinamide efficacy, optimise 5-FU regimens, and include more diverse populations to enhance generalisability.
Susanto et al. (Tue,) studied this question.