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 to their littermate controls (13.2 +/- 1.1 vs. 18.1 +/- 1.3, p = 0.006). Tumor diameter was also significantly smaller in Sprouty 2 overexpressors (0.85 mm +/- 0.03 vs. 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.