Nicotinamide, the amide form of vitamin B3, prevents photocarcinogenesis in mice and protects from the immunosuppressive effects of UVB and UVA radiation in humans. As an NAD+ precursor, nicotinamide is centrally involved in ATP production and cellular energy metabolism, which in turn regulates the highly energy-dependent process of DNA repair. Nicotinamide replenishes the ATP depleted in keratinocytes by UV exposure, and enhances repair of direct and oxidative DNA photolesions in cultured keratinocytes and in ex vivo human skin. In order to assess the in vivo effects of nicoitnamide on skin carcinogenesis, heavily sun damaged individuals were randomised to receive oral nicotinamide (500mg) or placebo twice daily for 4 months. Actinic keratoses (AKs) were counted by a blinded observer at baseline, 2 and 4 months. We found that participants receiving nicotinamide had reductions in AKs of 35% relative to placebo at 2 and 4 months (p<0.001). Similar relative reductions were observed in a second group receiving nicotinamide (500mg) or placebo once daily for 4 months. In total, 37 patients in these trials received nicotinamide and 37 received placebo. While 30% of the placebo group developed a new skin cancer during the study period (20 cancers in total), only 5% of those taking nicotinamide developed new skin cancers (4 cancers in total; p=0.019 for Logistic regression and p=0.010 for Poisson regression). A phase III doubled-blinded randomised controlled trial (ONTRAC; Oral Nicotinamide To Reduce Actinic Cancer) with an accrual target of 386 subjects is now underway. Otherwise healthy participants with at least 2 previous nonmelanoma skin cancers in the past 5 years receive nicotinamide 500mg or placebo twice daily for 12 months. AKs and new skin cancers are counted at baseline and 3 monthly. As a convenient tablet formulation, nicotinamide has the potential to provide a nontoxic, accessible and inexpensive (~$10/month) approach to skin cancer chemoprevention.