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Association between microsatellite instability (MSI) and favorable postoperative survival in patients with colorectal cancer receiving adjnvant chemotherapy has been indicated. To evaluate whether an analogous positive prognostic role of MSI could be present in rectal carcinoma (RC; most RC patients receive adjuvant radiotherapy), PCR-based microsatellite analysis of archival RCs and statistical correlation with clinico-pathological parameters were performed.DNA from paraffin-embedded paired samples of tumors and corresponding normal tissue from 91 RC patients was analyzed for MSI using five microsatellite markers (tumors were classified as MSI+ when two or more markers were unstable).Seventeen (19%) RC patients exhibited a MSI+ phenotype. Prevalence of instability was found in patients with earlier RC onset (28% in cases with diagnosis age ≤55 years versus 15% in cases >55 years), whereas similar MSI frequencies were observed in patients with different disease stage or receiving different adjuvant therapies. While MSI was detected in seven (64%) of 11 familial patients, a remarkably lower MSI incidence was observed in sporadic cases (10/80; 12.5%). A significant association with better disease-free survival (DFS) and overall survival (OS) was found for MSI+ patients (median DFS/OS, 30/32 months) in comparison to MSI− ones (median DFS/OS, 18/21 months) (P <0.001).MSI was demonstrated to be a strong molecular prognostic marker in rectal carcinoma, independent of the administered treatment (radiotherapy, chemotherapy or both).