The nicotinic 15q25 locus has been implicated in lung cancer risk, with an odds ratio of approximately 1.3. The same locus is associated with nicotine dependence due to cigarette smoking and with smoking-associated chronic obstructive pulmonary disease, which is a risk factor for lung cancer. Our meta-analysis of reported studies shows that this locus was not associated with lung cancer risk in >1000 never-smoker cases and >1800 controls. Review of exposure-response data for lung cancer risk showed that less than a half-cigarette per day may confer the same risk of lung cancer as that conferred by the 15q25 locus. Given the lack of effect in never-smokers and the known common and variable underreporting of smoking habit in studies on smoking-associated diseases, we cannot exclude that the association between the 15q25 locus and lung cancer risk is indirect, deriving from association of the same locus with smoking habit. Since nicotine is not carcinogenic, available data do not provide plausibility of the association between the nicotinic 15q25 locus and lung cancer pathogenesis. Thus, a direct link between the 15q25 locus and lung cancer risk has yet to be established.