Short tandem repeat (STR) polymorphisms in exon 4 of esophageal cancer related gene 2 (ECRG2) are a prognostic marker for squamous cell carcinoma (SCC) of the esophagus. The aim of the present study was to correlate these STRs with clinical outcome of the similar tumor type oral squamous cell carcinoma (OSCC). DNA of 81 patients that underwent complete surgical resection of OSCC was analyzed for STRs TCA3/TCA3, TCA3/TCA4 and TCA4/TCA4 in exon 4 of ECRG2 by PCR, capillary electrophoresis and DNA sequencing. ECRG2 STR TCA3/TCA3 were found in 45 (56%), TCA3/TCA4 in 33 (41%) and TCA4/TCA4 in 3 (3%) patients. TCA3/TCA3 was significantly associated with reduced relapse-free survival of OSCC, compared with TCA3/TCA4 and TCA4/TCA4 genotypes (P<0.05; log-rank test). TCA3/TCA3 STR was independent prognostic factor determined by multivariate Cox regression analysis (p<0.05). STR polymorphism TCA3/TCA3 in exon 4 of ECRG2 is associated with poor relapse-free survival in surgically completely resected OSCC patients and might be a potential prognostic marker.