The research was focused on testing the anticancer effects of Epigallocatechin-3-gallate (EGCG), the major tea catechin, in combination treatment with 5-fluorouracil (5-FU). It can be found in high content in the dried leaves of green or white tea and smaller quantities in black tea. Based on recent studies, previous data suggested that EGCG is responsible for much of the biological activity mediated by green tea, including cancer chemoprevention. Chemotherapeutic drugs and radiotherapy are commonly used in most cancer treatments, but they are toxic even for normal cells. However, the search for safe anti-cancer drugs at an affordable price is still a prime interest in cancer treatment. Natural compounds are a good choice in cancer management. The research was concentrated on testing the effects of EGCG on different cell lines derived from colorectal carcinoma, especially the lines harbouring the chemoresistance to 5-FU. The second aim was to reveal the affected signalling pathways involved in developing chemoresistance to 5-FU using combined therapy. The cells were cultivated in the presence of various concentrations of EGCG and 5-FU and their combinations. Cancer cells showed significant differences in the rate of proliferation in a concentration-related manner. Based on this finding, we aimed to describe signalling pathways and genes affected by EGCG. We concentrated on members of the Human ATP-binding cassette (ABC) transporter family, which are involved in the efflux of chemotherapeutic drugs out of the cells. We assumed that these changes are present only in chemoresistant cell lines. To confirm this, we compared the 5-FU resistant cell line HT-29/FUR gene expression with the HT-29 parental cell line. It is essential to know what is affected in the cells by any therapy to avoid side effects and set the proper treatment for each patient. The combined therapy of EGCG and 5-FU could be beneficial for patients suffering from refractory cancer in the future.