Background: Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers with COPD but the pathogenesis of SAR is not understood. Objective: To determine whether smoke causes production of profibrotic growth factors in the airway wall. Methods: We exposed C57Bl/6 mice to cigarette smoke for up to 6 months and examined growth factor/procollagen gene expression in laser capture microdissected small airways by real-time RT-PCR. Results: With a single smoke exposure, increases in procollagen, connective tissue growth factor (CTGF), transforming growth factor (TGF)-₁, platelet-derived growth (PDGF)-A and-B expression were seen 2 hours after the start of smoking and declined to baseline by 24 hours. With repeated exposures and sacrifice of animals 24 hours after the last exposure, increases in procollagen, CTGF, PDGF-B, and (minimally) PDGF-A, expression persisted through 1 week, 1 month, and 6 months. TGF₁ gene expression declined over time; however, increased immunochemical staining for phophos-Smad 2 was present at all time points, indicating continuing TGF downstream signaling. Morphometric analysis showed that the small airways in smoke exposed mice had more collagen at 6 months. Conclusions: These findings suggest that smoke can induce growth factor and procollagen production in small airways in a time frame that initially is too short for a significant inflammatory response and that profibrotic growth factor and procollagen gene expression become self-sustaining with repeated smoke exposures. These results imply that the pathogenesis of and possible treatment approaches to emphysema and small airway remodeling might be quite different.