Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD). A relevant animal model of COPD is needed to evaluate products with potentially reduced risk. The objective of this study was to assess the suitability of the strain a mouse as a model for cigarette-smoke-induced lung emphysema. Female A/J mice, 6 months old, were exposed to diluted mainstream smoke from the reference cigarette 2R4F for 2, 3, or 4 h/day, 5 days/week for 5 months. The mean smoke concentration throughout the study was 735 µg total particulate matter/l. After 5 months, pronounced lung inflammation was observed, as evidenced by increased numbers of neutrophils (37-fold) and lymphocytes (6-fold) in bronchoalveolar lavage fluid (BALF). Alveolar macrophages showed an increased activation status, as indicated by increased expression levels of CD11B (414-fold) and CD86 (10-fold). A large number of pro-inflammatory mediators in BALF were increased, especially neutrophil and monocyte chemoattractants (e.g., MIP2: 4-fold and MCP1: 94-fold). The most pronounced change in BALF was observed for IgA (149-fold), which suggests a humoral response. Lung inflammation was accompanied by increased levels of MMP9 (45-fold) and TIMP-1 (at least 6-fold) in BALF. No significant inflammation-related changes were observed in the bronchial lymph nodes or in serum. Pulmonary function measurements indicated an increased tissue elastance (up to +33%) and a decreased Paomax (up to -38%), which are indicative of structural changes in the lung. Morphometric measurements showed an increased mean chord length at the highest dose (+32%).