Knowledge on mechanisms of smoking-induced tumorigenesis and on active smoke constituents may improve the development and evaluation of chemopreventive and therapeutic interventions, early diagnostic markers, and new and potentially reduced-risk tobacco products. A suitable laboratory animal disease model of mainstream cigarette smoke inhalation is needed for this purpose. In order to develop such a model, A/J and Swiss SWR/J mouse strains, with a genetic susceptibility to developing lung adenocarcinoma, were whole-body exposed to diluted cigarette mainstream smoke at 0, 120, and 240 mg total particulate matter per m3 for 6 h per day, 5 days per week. Mainstream smoke is the smoke actively inhaled by the smoker. For etiological reasons, parallel exposures to whole smoke fractions (enriched for particulate or gas/vapor phase) were performed at the higher concentration level. After 5 months of smoke inhalation and an additional 4-month post-inhalation period, both mouse strains responded similarly: no increase in lung tumor multiplicity was seen at the end of the inhalation period; however, there was a concentration-dependent tumorigenic response at the end of the post-inhalation period (up to 2-fold beyond control) in mice exposed to the whole smoke or the particulate phase. Tumors were characterized mainly as pulmonary adenomas. At the end of the inhalation period, epithelial hyperplasia, atrophy, and metaplasia were found in the nasal passages and larynx, and cellular and molecular markers of inflammation were found in the bronchoalveolar lavage fluid. These inflammatory effects were mostly resolved by the end of the post-inhalation period. In summary, these mouse strains responded to mainstream smoke inhalation with enhanced pulmonary adenoma formation. The major tumorigenic potency resided in the particulate phase, which is contrary to the findings published for environmental tobacco smoke surrogate inhalation in these mouse models.