The aims of this study were to evaluate the prognostic implications of patients with epidermal growth factor receptor (EGFR) mutations and a p21 expression, and to determine their associations in resected non-small cell lung cancer (NSCLC) patients. We sequenced exons 18-21 of the EGFR tyrosine kinase domain by performing mutation analysis of tissues from patients that suffered with NSCLC and who also had undergone surgical resection. The expressions of p21 and p53 were analyzed using immunohistochemistry. We detected EGFR mutations in 24 of 97 patients (25%). EGFR mutations were more frequent in the people who had never smoked than in the smokers (33% versus 14%, respectively; P=.028). The presence of EGFR mutations had no effect on survival. The expression of p21 in the patients with wild-type EGFR tended to be associated with better survival. However, the expression of p21 in the patients with EGFR mutations was associated with poor overall survival (P=.006). The five-year survival rates were 17% for the patients with EGFR mutations and p21 positivity (Group I), 44% for the patients with wild type EGFR (Group II), and 75% for the patients with EGFR mutation and no p21 positivity (Group III) (P=.036). Multivariate analysis that was corrected for age, gender and cancer stage revealed different overall survival outcomes according to the three groups (P=.004). There was no significant correlation between the expressions of p21 and p53. Survival outcomes in the patients with resected NSCLC may be correlated with the presence of a p21 expression and EGFR mutations.