Objective To investigate the expression of p21, p53 and c-erbB-2 in tissues of non-small cell lung cancer (NSCLC), and explore its clinical significance. Methods The clinical data and paraffin tissue samples of 207 patients with NSCLC confirmed by postoperative pathology were collected. The expression of p21, p53 and c-erbB-2 protein in tissues of NSCLC was detected by immunohistochemical method, the correlation among the expression of p21, p53 and c-erbB-2 protein was analysed, and the relationship between the expression of p21, p53 and c-erbB-2 protein and clinicopathological characteristics was explored. Results The expression of p21 was significantly positively related to that of p53 in tissues of NSCLC （r=0.245，P<0.01）. The positive expression rates of p21, p53 and c-erbB-2 in tissues of NSCLC were 54.11%, 38.16% and 32.85%, respectively in 207 patients, and patients with poor differentiation, medium differentiation and lymph node metastasis had significantly higher expression than those with high differentiation and no lymph node metastasis (P<0.05). Patients with history of smoking, central type and squamous carcinoma had higher positive expression rates of p21 and p53, and females and those with no history of smoking, peripheral type and adenocarcinoma had higher expression rates of c-erbB-2 (P<0.05). The 5-year survival rates of patients with positive expression of p21, p53 and c-erbB-2 in tissues of NSCLC were significantly lower than those with negative expression (P<0.05). Conclusion p21, p53 and c-erbB-2 may play important roles in development and progression of NSCLC, which may serve as predicators for prognosis.