To determine whether preoperative natural killer (NK) cell activity has any prognostic significance in colon cancer patients. The study population consisted of 140 patients with colon cancer. NK cell activity was determined within 2 weeks before surgery in 128 patients and at the time of diagnosis in the remaining 12 patients who either did not undergo surgery or who underwent palliative surgery only. Disease progression and postoperative prognosis were examined in relation to NK cell activity. Decreases in NK cell activity did not necessarily correspond to tumor stage. In curatively operated stage I–III diseases, preoperative NK cell activity of 20% or less correlated with poor survival. Lower activity was also associated with metachronous distant metastases but not with local recurrences. In particular, more than half the stage III patients with attenuated NK cell activity developed metastases. Multivariate analysis indicated that attenuated NK cell activity was a significant parameter for predicting distant metastasis following curative surgery for colon cancer. Preoperative NK cell activity has a significant prognostic value in curatively operated colon cancer, particularly for the development of metachronous distant metastasis in stage III patients.