Inflammation plays a key role in the atherosclerotic process. As part of a study on the influence of cigarette mainstream smoke (ms) in combination with high-fat diet on the development of atherosclerosis, we investigated the inflammatory response and histopathological alterations in lungs from Apolipoprotein E-deficient (ApoE -/-) mice, a classic model for atherosclerosis. Male ApoE -/- mice were whole-body exposed for 12 months (6 h/d, 5 d/wk) to diluted MS at total particulate matter (TPM) concentrations of 100 and 200 μg/l or to filtered fresh air. Each exposure group was fed either a chow diet or a milk-fat-enriched diet. Bronchoalveolar lavage (BAL) was performed and inflammatory cells were quantified in BAL fluid (BALF); lungs were evaluated histopathologically. Mice exposed to 100 μg TPM/l MS showed no statistically significant inflammatory and epithelial changes in the lung. Mice exposed to 200 μg TPM/l MS showed statistically significant inflammatory changes, i.e., a constant elevation of neutrophils and a continuous increase in lymphocytes in BALF with both diets. In the high-fat diet groups, there was a tendency to a greater increase in neutrophils and lymphocytes. Pathomorphological findings observed in the lungs of mice exposed to 200 μg TPM/l MS included multifocal alveolar histiocytosis present as single macrophages and pigmented macrophage nests (PMN). Hypertrophy/hyperplasia of the alveolar epithelium was seen only in single cells directly associated with the PMN. The incidence of these pathomorphological findings increased from 20% after 3 months of exposure to 80% after 12 months of exposure in both diets. Interstitial lymphocytic infiltrates were present in 80% of these mice only after 12 months of exposure. The pathomorphological alterations were not influenced by high-fat diet. In summary, our data indicate that chronic exposure of ApoE -/- mice to 200 μg TPM/l MS results in non-neoplastic pathomorphological changes in the lung and an inflammatory response, which is a mixture of innate and adaptive immune responses, as indicated by an increase in BALF neutrophils and lymphocytes.