BACKGROUND & AIMS. The present study was designed to examine the combined effects of Oxaliplatin (OXA) and 5-Fluorouracil (5-FU) in the Colo320 cell line. METHODS. The antiproliferative effects were evaluated using the MTT assay, apoptosis by flow cytometry, and RT-PCR-array technology was used to determine the major effects of the two chemotherapeutic drugs upon the most important genes involved in apoptosis. RESULTS. The antiproliferative effects of the therapeutic agents, as individual therapy or combined, proved to be dose and time-dependent, with increased efficiency for the combined treatment. Flow cytometry data revealed increased apoptotic processes in the case of the combined treatment at 24 hours after administration. The RT-PCR-array data indicated that at 24 hours after OXA treatment, 49 genes were differentially expressed, of which 45 were up-regulated and 4 down-regulated. In the case of the 5-FU treatment, 35 genes were down regulated and 2 up regulated. In the combined treatment of 5-FU and OXA, 19 genes were up-regulated and 15 down-regulated. CONCLUSIONS. This study proved that drug resistance could be counteracted by combining OXA with 5-FU to form a tandem that is capable of reducing cell proliferation and to stimulate extrinsic apoptosis pathway by targeting death receptors on the cell surface.