There is no clear evidence on the prognostic and predictive value of abnormal p53 expression in colorectal cancer. The major downstream protein, p21, a cell cycle inhibitor, is transcriptionally regulated by p53. The prognostic impact of p21 expression in colorectal carcinomas is still under debate. In this study, we investigated the expression of p21 and p53 in a prospective cohort of 116 sporadic colorectal carcinomas at UICCII/III stage. We observed an expression of p21 in 26% and p53 in 63% of the carcinomas by immunohistochemistry. Patients with p21-negative colorectal carcinomas had a significant better recurrence-free and overall survival than patients with p21-positive carcinomas (p=0.02 and p=0.005). Expression of p53 was related to a better overall survival (p=0.048). The combination of p21-negative/p53-positive expression was significantly related to better recurrence-free and overall survival (p=0.007 and p=0.0001) and gained independent prognostic significance (HR: 3.4, p=0.01). Moreover, patients with combined p21-/p53+ expression had a remarkable benefit in overall survival after adjuvant chemotherapy as compared to the p21-/p53- subgroup (HR: 3.6, p=0.027). Our data suggest that the assessment of both p53 and p21 expression may provide prognostic information in colorectal cancer patients. This combination might be helpful to identify patients who could benefit from chemotherapy.