We examined whether overexpression of p53 can be used as a new genetic marker to predict the presence of lymph node metastases of early invasive colorectal cancer. Forty-nine patients with primary colorectal adenocarcinomas invading to the submucosa (sm-CRC) were analyzed and 7 patients were found to have lymph node metastases. Immunostaining was used to detect the p53 overexpression; 43% of sm-CRC stained positive for p53 and all the cancer cells metastasized to lymph nodes were p53 positive. Both lymph node involvement and tumor budding were significantly more frequent in p53 positive than p53 negative tumors (p < 0.05, respectively), and multivariate analysis showed that p53 overexpression constituted a higher relative lisk for lymph node metastases of sm-CRC than either histologic type, level of sm invasion, macroscopic type, tumor budding or vascular invasion, although the difference was not significant (p = 0.086). We concluded that p53 overexpression is a useful biological marker of lymph node metastases of sm-CRC, and that p53 negative status may be an indicator for limited surgery, such as local excision of sm-CRC.