Members of the Sprouty family encode novel proteins that are thought to function primarily as intracellular antagonists of the Ras-signaling pathway. Increased Ras signaling is a critical characteristic of human lung adenocarcinoma, the most common type of non-small cell lung cancer. Sprouty 2 is expressed in the lung epithelium, the tissue layer from which lung cancers arise. We hypothesized that overexpression of Sprouty 2 in the distal lung epithelium would inhibit lung tumorigenesis. To test the hypothesis, the consequences of overexpressing Sprouty 2 in the distal lung epithelium on urethane-induced mouse lung tumorigenesis were determined. Urethane is a chemical carcinogen found in tobacco smoke that causes activating mutations in Kras and induces lung tumors in mice. Sprouty 2-overexpressor mice developed significantly fewer lung tumors compared with their littermate controls (13.2 ± 1.1 versus 18.1 ± 1.3, P = 0.006). Tumor diameter was also significantly smaller in Sprouty 2 overexpressors (0.85 mm ± 0.03 versus 0.95 mm ± 0.02, P = 0.005). Sprouty 2 overexpression did not alter Kras mutational frequencies in urethane-induced tumors, suggesting that the tumor-suppressing effect of Sprouty 2 overexpression acts at a stage after Kras mutation, perhaps by interfering with receptor tyrosine kinase-induced signaling. These results demonstrate that Sprouty 2 overexpression inhibited both tumor initiation and subsequent tumor growth.