AIM: To examine the expression of thymidylate synthase (TS) and oncoprotein Bcl-2 in advanced colorectal cancer (CRC) patients, and to determine their mutual relationship, association to therapeutic response and impact on disease outcome. METHODS: Tumor samples from 67 patients with CRC, who were treated at advanced stage with either irinotecan alone or in combination with 5-fluorouracil/ leucovorin, were analyzed for expression of TS and BCl-2 using immunohistochemistry. RESULTS: A significant linear correlation between lower expression levels of Bcl-2 and lower levels of TS expression was found (P=0.033). Patients with high levels of both TS and Bcl-2 expression had a significantly longer disease-free survival (DFS) (42.6 mo vs 5.4 mo, n=25) than those with low TS/Bcl-2 index (P=0.001). Tumors with low levels of both TS and Bcl-2 were associated with a longer survival with metastasis (WMS) interval in the whole patients group (η = 67, P = 0.035). TS/Bcl-2 index was not significantly related to disease-specific survival. CONCLUSION: The present data suggest that CRC patients with low TS/Bcl-2 demonstrate a significantly shorter DFS and longer WMS. 2008 The WJG Press. All dghts reserved,Key words: Thymidylate synthase, Bcl-2; Colorectal cancer; Disease-free survival; Survival with metastaseis Peer reviewers: Shu Zheng, Professor, Scientific Director of Cancer Institute, Zhejiang University, Secondary AffiliatedHospital, Zhejiang University, 88# Jiefang Road, Hangzhou 310009, Zhejiang Province, China; Lars A Pahlman, Professor,Department of Surgery, Colorcctal Unit, University Hospital,SE 751 85, Uppsala, Sweden; Damian Casadesus, MD, PhD,Calixto Garcia University Hospital, J and University, Vedado,Havana City, Cuba Bendardaf R, Ristamaki R, Syrjanen K, Pyrhonen S. Bcl-2 expression significantly correlates with thymidylate synthase expression in coiorectal cancer patients. World J Gastroenterol.