Monoclonal antibody-directed therapy has been used as an effective treatment for some cancers that overexpress HER2/neu and vascular endothelial growth factor (VEGF). Overexpression of the HER2/neu oncogene and VEGF has been reported to occur in adenocarcinomas of the colon. Assessing whether HER2/neu and VEGF overexpression could serve as prognostic indicators for stage II colon cancer may provide insight into optimal treatment following surgery. Demographic and tumor characteristics from 109 patients diagnosed with stage II colon cancer between 1991 and 1996 were assessed for HER2/neu and VEGF expression using immunohistochemical staining techniques. Of the 109 cases, 107 (98%) were histologically classified as adenocarcinomas, 105 (96%) were grades 2/3, and 105 (96%) were stage T3. Only 12 cases (11%) exhibited HER2/neu overexpression and 72 cases (66%) exhibited VEGF expression. There was no significant difference in overall survival or in time to recurrence between the groups with and without HER2/neu overexpression. There was a trend toward decreased overall survival with VEGF expression (P = 0.07), but no difference in time to recurrence (P = 0.63). There were 18 patients who received adjuvant chemotherapy, but removal of these patients from the analysis did not change the results. There was no association between HER2/neu and VEGF expression and patient demographics or tumor characteristics, with the exception of VEGF expression and mucinous histology (P < 0.01). Our results do not support an association between HER2/neu or VEGF expression and overall survival or time to recurrence in stage II colon cancer. With further investigation, a significant correlation may be found between VEGF expression and prognosis, and thus direct therapy with a monoclonal antibody.