β-carotene is a naturally occurring and safe dietary source of vitamin A that is associated with cancer risk reductions when consumed in typical dietary amounts. However, two clinical trials reported increased incidence of lung cancer and total mortality among heavy smokers taking β-carotene supplements (20 or 30 mg/day). Based on these findings, the Joint FAO/WHO Expert Committee on Food Additives withdrew Acceptable Daily Intake values for β-carotene (0-5 mg/kg bw). We evaluated relevant epidemiological and toxicological literature to assess the biological plausibility of this relationship and identified three mechanisms involving cellular proliferation signaling, a mode of action for cancer promotion. The overall weight of evidence consistently demonstrated typical dietary doses of β-carotene decreased cellular proliferation signaling via these mechanisms, even in the presence of smoke, while co-exposure to smoke and higher, supplemental doses increased cellular proliferation signaling through these same pathways. The production of excessive oxidative β-carotene metabolites via reactions with smoke constituents may be a key event underlying this relationship. Consistent with previous findings, our evaluation indicated consumption of up to 50 mg/day β-carotene does not present safety concerns for the non-smoking general population. Heavy smokers consuming less than 15 mg β-carotene/day are not expected to be at an increased risk of lung cancer.