Despite the causality between human smoking and lung cancer (IARC, 2004), establishing reproducible and validated animal inhalation models for lung cancer induced by tobacco smoking has proven difficult. Here we report on two mouse strains suggested as possible models for lung tumorigenicity. Male A/J mice and Swiss SWR mice were whole-body exposed to diluted mainstream smoke from the standard reference cigarette 2R4F or to filtered fresh air (control), 6 hours per day, 5 days per week for 5 months, followed by a post-exposure period of 4 months. Smoke exposure was to whole smoke at concentrations of 120 or 240 microg total particulate matter (TPM)/L, to gas phase-depleted particle phase at 240 microg TPM/L, or to gas phase at a carbon monoxide concentration equivalent to 240 microg TPM/L. Lung tumor incidence and multiplicity were determined in the control and 240 microg TPM/L whole smoke groups at the end of the exposure period and in all groups at the end of the post-exposure period. At the end of the 5-month exposure period, a severe increase in neutrophils and macrophages in bronchoalveolar lavage fluid, indicating inflammation, was seen in the whole smoke groups. By the end of the 4-month post-exposure period, both inflammatory cell types had returned nearly to background levels. At the end of the 5-month exposure period, there was no difference in lung tumor response between smoke-exposed and control mice in both mouse strains. An enhanced lung tumor response was seen only after the 4-month post-exposure period: lung tumor incidence and multiplicity in the whole smoke groups was dose-dependently higher compared to controls by a factor of up to approximately 3-fold in A/J mice and a factor of up to approximately 2-fold in Swiss SWR mice. In A/J mice the lung tumor response was similar for gas phase-depleted particle phase and whole smoke at the same TPM concentration. In Swiss SWR mice, gas phase-depleted particle phase accounted for approximately 50% of the lung tumor response in the whole smoke group at the same TPM concentration. Gas phase failed to enhance lung tumor incidence and multiplicity in both mouse strains compared to controls. Microscopic examination of lung step serial sectioning in selected groups confirmed the macroscopic lung nodule assessment. Smoke exposure did not change the spontaneous lung tumor spectrum; Bronchiolo-alveolar adenoma was the most prominent lung tumor type. There appears to be a need for a post-exposure period to see an increase in lung tumor incidence and multiplicity in both mouse strains. Further research is needed to evaluate the relevance of these models with regard to the human disease.