Ras/ERK and PI3K/Akt pathways are reported to play a prognostic role and contribute to drug resistance in many cancers. The objective of this study was to explore associations between the expression levels of several molecules in Ras/ERK and PI3K/Akt pathways and their clinical significance in predicting the effectiveness of postoperative adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC). The expressions of K-ras, Raf-1, ERK1/2, phosphorylated ERK1/2 (pERK1/2), Akt-1, phosphorylated Akt-1 (pAkt-1), and Bcl-2 were detected by immunohistochemistry in tumor specimens from 144 NSCLC patients. The correlations between the expression levels of these molecules and the clinicopathological characteristics were analyzed. Patient survival was analyzed by Kaplan-Meier method, log-rank test, and Cox regression. The positive expression rates of K-ras, Raf-1, ERK1/2, pERK1/2, Akt-1, pAkt-1, and Bcl-2 were 21.5%, 41.7%, 59.7%, 27.1%, 50.7%, 36.1%, and 30.6%, respectively. Univariate analysis showed that patients with pERK1/2-positive (P = 0.01), Bcl-2-positive (P = 0.023), or pAkt-1 negative (P = 0.021) had significantly better recurrence-free survival (RFS) than those with pERK1/2-negative, Bcl-2-negative, or pAkt-1-positive. Multivariate analysis showed that earlier stage (P ≤ 0.001), non-adenocarcinoma (P ≤ 0.001), pERK1/2-positive (P ≤ 0.001), and pAkt-1-negative (P = 0.016) were independent prognostic factors for a better RFS in NSCLC. pERK1/2-positive and pAkt-1-negative proved to contribute to a better RFS in postoperative NSCLC patients who received adjuvant chemotherapy after taking the stage and histological subtype into account. pERK1/2 and pAkt-1 could be considered as new independent prognostic biomarkers for predicting RFS and selecting patients who are more likely to benefit from postoperative adjuvant chemotherapy.