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Objective: The aim of this study was to investigate the expression and clinical significance of ras-p21 and p53proteins in inguinal lymph nodes with penis carcinoma. Methods: The clinical data of 44 patients of penis (squamous) carcinoma and 40 non-tumor patients from 1990 to 2002 in our hospital were added to our research, 84 inguinal lymph nodes were got by lymph node biopsy from each patient at random. Pathological examination showed that 18 cases of cancer group were metastatic carcinoma as group A, the other 26 cases were inflammatory affection as group B. 20 cases of non-tumor group were nonspecific inflammatory inguinal lymph nodes as group C and the other 20 cases were normal lymph nodes as group D, all the 84 cases in our research were investigated by immunohistochemistry to detect the expression of ras-p21 and p53protein. Results: Immunohistochemistry demonstrated that the expression of as-p21 and p53 protein were significantly higher in cancer group A (88.89%, 72.22%) and B (30.77%, 23.08%) than in control group C (5%, 0%) and group D (0%, 0%.). The expression of two proteins showed significant differences between group A and group B (P ＜ 0.01), and no significant differences between group B and group C (P ＞ 0.05). The expression of two proteins showed significant difference between group A and control group (C + D) (P ＜ 0.01). The expression of two proteins showed significant differences between cases of cancer groups (A + B) and control groups (C + D) (P ＜ 0.01). Significant differences were showed between group (A + B) and group D with the expression of ras-p21 and p53 (P ＜ 0.01). The expression of ras-p21 and p53 in three different differentiated groups were G1 (well-differentiated) group: (22.73%, 13.64%), G2 (moderate-differentiated) group: (81.25%, 68.75%), G3 (poorly differentiated) group: (100%, 83.33%). There was significant differences between G1 group and G3 group (P ＜ 0.05), and no significant differences between G1 group and G2 group, G2 group and G3 group (P ＞ 0.05). There was significant differences between three clinical stages with the expression of ras-p21 and p53 (P ＜ 0.05). Conclusion: Ras-p21 and p53 protein werehighly expressed in cancer groups in this study, while, two proteins hardly detected from control groups. If the inflammatory lymph nodes of penile cancer patients show the positive expression of p21 and p53 protein, the inguinal lymph nodes also need dissection, which is important to improve the diagnosis of inguinal lymph node metastasis rate and patient survival of penile cancer. Ras-p21 and p53 protein detection can act an objective indicator of tumor metastasis and prognosis, and also for our treatment of penile cancer in the inguinal lymph node dissection surgery provides determine indicators.