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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 (n = 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.