Evaluating the state of malignancy of thymoma is a challenge due to the discrepancies between pathological classifications and clinical stage criteria. Therefore, the identification of markers contributing to the assessment of the stage of malignancy of thymoma would be useful. This study aimed to evaluate the prevalence of p53 and epidermal growth factor receptor (EGFR) in thymoma, demonstrate the clinical significance and assess the potential of specific-targeted therapy. A total of 16 thymic hyperplasia patients and 43 thymoma patients were included in the study. Samples were tested for the expression of p53 and EGFR using immunohistochemistry. In the multivariate analysis, the thymoma cases were followed up to analyze the relationship between survival rates and a number of potential factors, such as p53 and EGFR. There were 21 completely resected stage II cases which were evaluated for relapse-free time. The distribution of p53 with clinicopathological parameters was: type A/AB 57.1%, type B1 85.7%, type B2 85.7%, type B3 90.9% and type C 100%; and stage I 90.9%, stage II 90.9%, stage III 100% and stage IV 100%. The EGFR-positive rates were: type A/AB 42.9%, type B1 71.4%, type B2 57.1%, type B3 90.9% and type C 100%; and stage I 45.5%, stage II 76%, stage III 75% and stage IV 100%. EGFR expression correlated with tumor size, pathological classification and advanced clinical stage, whereas p53 correlated only with pathological classifications. Findings of our multivariate analysis showed that neither p53 nor EGFR are independent prognostic factors. Nevertheless, the fact that a statistical difference (p<0.05) was noted in relapse-free survival time between the EGFR-positive and EGFR-negative groups (48.182±33.757 vs. 76.3±10.339 months) suggests that EGFR plays a key role in thymoma progression. No positive results were found between the p53 groups following a survey conducted to assess relapse time. Therefore, the application of EGFR-targeting agents is warranted in invasive thymoma, whereas the targeting of p53 has yet to be elucidated.