Specific-pathogen-free female F344 rats were exposed by inhalation to what was considered a maximal tolerated dose of cigarette smoke. Total pulmonary deposition of smoke particulates from a single cigarette was 0.25 mg in young rats. Rats were exposed to smoke from 7 cigarettes/day for as long as 2.5 years, at which time 30% of the rats remained alive. Mortality of smoke-exposed animals was not different from that of untreated or sham-exposed controls. Hyperplastic and metaplastic areas in the epithelium of the nasal turbinates, larynges, and tracheae of exposed animals were observed at death. The lungs of exposed rats contained areas of focal alveolitis consisting of accumulated pigmented macrophages, epithelial hyperplasia, fibrosis, and disrupted alveolar structure. Smoke exposure did not change the total number of tumor-bearing animals relative to controls; however, exposed rats had significantly fewer tumors in the hypophyses, hematopoietic-lymphoid systems, uteri, and ovaries but an increased number of tumors in the respiratory tracts and dermes. Only 1 of 93 (1%) control rats had a tumor (an alveologenic carcinoma) in the respiratory tract as opposed to 7 of 80 (9%) exposed animals (nasal tumors: 1 adenocarcinoma and 1 squamous cell carcinoma; pulmonary tumors: 5 adenomas, 2 alveologenic carcinomas, and 1 squamous carcinoma).