Summary P-carotene has been hypothesised to reduce lung cancer risk. We studied the effect of 14 weeks of P-carotene supplementation (20 mg d-1) on the frequency of micronuclei in sputum in 114 heavy smokers in a double-blind trial. Micronuclei reflect DNA damage in exfoliated cells and may thus provide a marker of early-stage carcinogenesis.Pre-treatment blood levels of cotinine, P-carotene, retinol and vitamins C and E were similar in the placebo group (n = 61) and the treatment group (n = 53). Plasma 1-carotene levels increased 13-fold in the treatment group during intervention. Initial micronuclei counts (per 3,000 cells) were higher in the treatment group than in the placebo group (5.0 vs 4.0, P<0.05). During intervention, the treatment group showed a 47% decrease, whereas the placebo group showed a non-significant decrease (16%). After adjustment for the initial levels, the treatment group had 27% lower micronuclei counts than the placebo group at the end of the trial (95% CI: 9-41%).These results indicate that P-carotene may reduce lung cancer risk in man by preventing DNA damage in early-stage carcinogenesis.The scientific interest in the role of carotenoids and retinoids in the prevention of human cancer has culminated in recent years (Editorial, 1991;Meyskens, 1990 al., 1987;Fontham, 1990). Since these studies cannot prove causal associations, two large randomised trials are currently conducted to evaluate the beneficial effect of P-carotene on human cancer development (Hennekens & Eberlein, 1985;Albanes et al., 1986). These intervention studies, however, provide little information on biological mechanisms.Damage to DNA is considered a crucial mechanism in cancer development (Weinstein, 1988). Micronuclei, DNA fragments in exfoliated cells, may thus provide a marker of early-stage carcinogenesis in target tissues (Lippman et al., 1990a,b;Stich et al., 1984a). In cigarette smokers, elevated micronuclei counts in expectorated sputum (Fontham et al., 1986) or bronchial brushings (Lippman et al., 1990a) are thought to reflect increased lung cancer risk.So far, no studies have investigated the effect of P-carotene supplementation on sputum micronuclei, as a reflection of lung cancer risk. P-Carotene has been shown to reduce micronucleated buccal mucosal cells in tobacco chewers (Stich et al., 1984a(Stich et al., , 1985(Stich et al., , 1988 and may thus reduce risk for oral cancer. These trials, however, did not measure plasma levels of P-carotene and retinol. Moreover, other antioxidant vitamins may modify the effects of P-carotene (Meyskens, 1990 Blood and sputum samples were collected before and after the 14-week treatment. The participants were instructed to take capsules daily with the evening meal, two capsules per day during the first 2 weeks, followed by one capsule per day over the next 12 weeks. Every 4 weeks, the participants were sent their next strip of 28 capsules, and were asked to return the used strips with the capsules not taken to monitor compliance. In addition, P-carotene was determined...