Objective: Impaired signal transduction is associated with tumorigenesis and progression of various kinds of human cancers. Transforming growth factor (TGF)-beta/Smad and ras-mitogen activated protein kinase (MAPK) are two major signal transduction pathways for adjusting cell proliferation and differentiation. Little is known about TGF-beta/Smad4 in non-small cell lung cancer (NSCLC). Hereby, we investigated the expression of Smad4 in NSCLC, its correlation with MAPK proteins (including p38, ERK1 and JNK1 proteins) and their clinical significance in NSCLC. Methods: The expressions of Smad4, p38, ERK1 and JNK1 were detected at protein level with West blotting and immunohistochemistry, at transcription level with RT-PCR. Statistical analysis was performed for the comparisons of expressions of Smad4, p38, ERK1 and JNK1, and their correlation with various clinicopathological parameters and the prognosis of NSCLC. Results: The levels of protein and mRNA expression of Smad4 in lung cancer tissues were significantly lower than in normal tissues (P＜0.05). All these four proteins were associated with TNM staging. There was a strongly negative correlation between p38 and Smad4. Expressions of Smad4, p38 and JNK1, as well as tumor differentiation and staging were significantly correlated with the prognosis of NSCLC by univariate analysis. By multivariate analysis, only Smad4, p38, tumor differentiation and staging were correlated with the prognosis. Taken together, the negative expression of p38 and positive expression of Smad4 were associated with a better prognosis of NSCLC. Conclusion: Smad4 could be of vital importance for the initiation and development of NSCLC. The expression of Smad4 might be inhibited by p38, supporting a cross-talk between main proteins of TGF-beta/Smad and ras-MAPK signal transduction pathways. Smad4 and p38 could be possible prognostic factors for NSCLC.