Objective: To determine the DNA replication error (RER) status in young patients with colorectal cancer (CRC), and to compare the clinical and pathologic characteristics of RER-positive and RER-negative cases. Summary Background Data: Recent studies suggest that patients with RER-positive CRC have an improved prognosis. Further data are required to confirm this observation in young CRC patients. Methods: All patients 40 years of age and younger with CRC admitted to the National Naval Medical Center between 1970 and 1992 were considered for inclusion in the study. After review, 36 patients for whom the original archived pathology specimen could be retrieved served as the study population. The RER status was determined using a previously described polymerase chain reaction-based assay. The clinical and pathologic features and survival data were compared to RER status. Results: RER-positive tumors were found in 17 cases (47%). There was no significant difference in Dukes' stage or histologic grade at the time of diagnosis between patients with RER-positive tumors compared to RER-negative tumors. Patients with RER-positive tumors were found to have an improved prognosis: the 5-year survival probability for patients with RER-positive tumors was 68%, as compared to 32% for patients with RER-negative tumors (p < 0.05). Conclusions: RER-positive tumors are common in young patients with CRC, and patients with RER-positive tumors have a significantly improved prognosis. Because of their young age, survival data and prognosis play an important role in the overall treatment plan of young patients with CRC. Therefore, knowledge of RER status could affect initial therapy, postoperative chemotherapy, and follow-up.