A laboratory animal model for cigarette-smoke-induced pulmonary tumorigenesis is needed to unravel mechanistic and etiologic aspects of the disease, to investigate chemopreventive and early diagnostic means, and to evaluate risks from novel tobacco products. Here, we show the first reproducible series of studies using cigarette mainstream smoke (MS) inhalation in mice (whole-body, 6 h/d, 5 d/w). Male A/J mice exposed to up to 300 mg/m(3) total particulate matter for 18 months showed dose-dependent increases in the multiplicity of pulmonary adenomas (up to 5-fold) and adenocarcinomas (up to 2-fold). With shorter inhalation periods (5 or 10 months), increases in tumor multiplicity were seen only when the inhalation was followed by post-exposure periods (4 to 13 months; maximum overall duration of studies: 18 months). Lung tumor multiplicity was also increased in male Swiss SWR mice after 5 months of inhalation followed by a 4-month post-exposure period. For both A/J and Swiss mice, the tumorigenic potential was associated mainly with the MS particulate rather than the vapor phase. Tumorigenesis in A/J mice was associated with inflammatory processes indicated by changes in gene expression in lung tissue as well as increased molecular and cellular markers in the bronchoalveolar lavage fluid. Some of these changes reversed during post-exposure. Thus, chronic MS inhalation reproducibly increased lung tumorigenesis in A/J mice under conditions which allow the full development of the tumorigenic potential. Further investigations are needed to qualify the biological relevance of the model.