Cigarette smoking is a major cause of lung cancer; however, it has been difficult to reproduce the tumorigenicity of cigarette smoke in preclinical animal models. Increased lung tumorigenicity has been reported in strain a (A/J) mice exposed for 5 months to cigarette mainstream smoke (MS) followed by 4 months without further exposure, but not in mice exposed for 9 months. Here we report on long-term (18-month) whole-body exposure (6 h/day, 5 d/wk) of male A/J mice to MS at total particulate matter (TPM) concentrations of 150 and 300 mg/m(3) or to fresh air (sham). Classical histopathological evaluation of step-serial sections identified nodular alveolar hyperplasias, bronchiolo-alveolar adenoma, and carcinoma in all groups. Lung tumor multiplicity calculated from the histopathological evaluation indicated increases of up to 5-fold for adenomas and 2-fold for carcinomas in the MS-exposed groups. Tumor nodules and surrounding normal lung tissue were microdissected from all groups. RNA array analysis of the normal lung tissue revealed the expression of several MS-exposure-related genes, such as those involved in oxidative stress, sustained inflammatory effects, and xenobiotic metabolizing pathways. MS exposure did not significantly change the K-RAS mutation pattern in the three “hot spot” codons (12, 13, and 61) in the tumor nodules. Our data show that long-term inhalation of MS in the A/J mouse is a promising model for cigarette-smoke-related lung cancer. Further investigations are warranted to qualify the biological relevance of the model.