Nicotinamide (vitamin B3) plays an important role in cellular DNA repair. It is a substrate and inhibitor of PARP enzyme, which is activated by UV radiation and repairs DNA. After UV exposure, ATP is depleted in keratinocytes. Nicotinamide, as an NAD precursor, replenishes ATP in cultured human keratinocytes and in ex vivo skin and enhances the highly energy-dependent process of DNA repair. In mice, nicotinamide has been shown to prevent carcinogenesis and in human volunteers it has been shown to provide protection against UVB and UVA radiation-induced immunosuppression. In 76 heavily sun-damaged individuals participating in Phase 2 studies, nicotinamide at 500mg or 1000mg daily significantly reduced premalignant actinic keratoses (AKs) by ~30% relative to placebo within 2-4 months. Subjects randomised to receive oral nicotinamide also developed significantly fewer new nonmelanoma skin cancers (NMSCs) during the 4 month trials than those receiving placebo (p=0.019 Logistic regression and p=0.010 Poisson regression). Based on these promising preliminary data, a phase 3 double-blinded randomised controlled trial (ONTRAC; Oral Nicotinamide To Reduce Actinic Cancer) is currently underway with an accrual target of 386 subjects. Otherwise healthy subjects with at least 2 previous NMSCs in the past 5 years are randomised to receive nicotinamide 500mg or placebo twice daily for 12 months. AKs are counted at baseline and 3 monthly and new skin cancers are recorded. The primary endpoint is NMSC (SCC + BCC) count at 12 months. Secondary endpoints include SCC and BCC counts at 3, 6, 9, 15 and 18 months; AK counts at 3, 6, 9 and 12 months compared to baseline; SCC grades; and BCC subtypes. This trial aims to establish nicotinamide as an inexpensive (~$10/month), accessible and convenient (tablet formation) approach for skin cancer chemoprevention.