Despite the causality between tobacco smoking and lung cancer reported by IARC (2004), establishing reproducible and validated animal inhalation models for this disease has proven difficult. Here we report on the A/J mouse as a possible model for lung tumorigenicity. Male A/J mice were whole-body exposed to diluted cigarette mainstream smoke from the standard reference cigarette 2R4F or to filtered fresh air (control) for 6 hours per day, 5 days per week for 5 months followed by 4 months without exposure. Smoke exposure was to whole smoke at concentrations of 0.12 or 0.24 mg total particulate matter (TPM)/I, to gas phase-depleted particle phase (PP) at 0.24 mg TPM/I, or to the gas phase (GP) at a carbon monoxide concentration equivalent to 0.24 mg TPM/I. Lung tumor incidence and multiplicity were determined at 5 months in the control group and the whole smoke high concentration group and at 9 months in all groups. At 5 months, there was no difference in tumor response; however, a distinct inflammation was indicated in the whole smoke group by a severe increase in neutrophils and macrophages in bronchoalveolar lavage fluid. At 9 months, both cell types had returned nearly to background levels; however, lung tumor multiplicity in the whole smoke groups was dose dependency higher by a factor of up to 3-fold compared to control. The lung tumor response was similar for PP and the high concentration of whole smoke. GP failed to enhance lung tumor multiplicity in this study. Step-serial lung section analysis confirmed the macroscopic results. The lung tumor spectrum was the same in all groups with bronchiolo-alveolar adenoma being the most prominent lung tumor type. Further research is needed to evaluate the relevance of this model with regard to the human disease.