Whilst individual planning of treatment and follow-up in every colorectal cancer case is an increasing demand, prognostic markers are needed for predicting cancer progression in the primary phase. We studied the effect of replication error (RER)-positivity on colorectal cancer progression by analysing 255 colorectal cancer specimens by polymerase chain reaction (PCR) and fragment analysis and correlating the results with the clinical and histological features of the tumour and with patient outcome. RER-positivity was detected in 12% (28/235) of cases. It was associated with proximal location of the tumour (P < 0.001), poor differentiation (P = 0.001) and large tumour size (P = 0.009). The 5-year cumulative survival rate of the patients with RER-positive cancer of the proximal colon was markedly better (100%) than that of those with RER-negative proximal cancer (74%), whilst in cases of cancer of the distal colon or rectum, RER-positivity (21%) indicated poorer survival than RER-negativity (57%). Thus, it is suggested that RER-positivity has an opposite impact on cancer progression in cases of proximal and distal cancers. RER-positivity appears to indicate improved prognosis only in cases of proximally located cancer, in which it could accordingly be useful as a prognostic marker.