Adjuvant chemotherapy has been shown to alter the natural history of patients with resected colon cancer. Two regimens (fluorouracil [5-FU] plus levamisole (Ergamisol) and 5-FU plus leucovorin) have been found most successful in prolonging disease-free and overall survival. When these two regimens were directly compared in randomized clinical trials, it appeared that a small disease-free survival and overall survival advantage had emerged in favor of 5-FU plus leucovorin. This advantage, in conjunction with an increased understanding of the mechanism of leucovorin's biochemical modulation of 5-FU, makes this regimen a logical choice for studies designed to further optimize and augment the clinical efficacy of chemotherapy for colon cancer. The introduction of oral tegafur and uracil (UFT) and the demonstration of significant antitumor activity with the combination of oral UFT and oral leucovorin, provide an excellent opportunity to optimize treatment with 5-FU plus leucovorin. The National Surgical Adjuvant Breast and Bowel Project has recently implemented a new clinical trial (Protocol C-06) comparing oral UFT plus leucovorin with 5-FU plus leucovorin in the treatment of patients with resected stage II and III colon cancer. The rationale for the design of the trial, inclusion and exclusion criteria, treatment regimens, and statistical considerations are reviewed.