We previously reported that the combination of cis-diamminedichloroplatinum (CDDP) and 1-beta-D-arabinofuranosylcytosine (ara-C) induced a remarkable synergistic killing effect on an established human colon carcinoma cell line, LoVo. The current study investigated whether this effect was LoVo specific or could be extended to other colon cancer cell lines as well as to cell lines of different histological origins, including an estrogen receptor-positive breast cancer cell line (MCF7), an ovarian cancer cell line (OV1225), and an esophageal cancer cell line (Hcu18). The six human colorectal cancer cell lines included in this study represent three biological groups with distinct phenotypic properties. Group 1 (well-differentiated) consisted of LoVo and SW48; group 2 (intermediately differentiated) comprised SW480 and SW620; and group 3 (undifferentiated) was represented by SW403 and SW1116. No significant synergistic cytotoxicity was noted after the breast and ovarian cancer cells were treated. However, synergistic lethal effects were observed in all of the six colon cancer cell lines as well as the esophageal cancer cell line. The synergistic effect on the gastrointestinal cancer cell lines was related to the concentration of ara-C and CDDP during treatment. Our results suggest that the cytotoxic synergism between ara-C and CDDP may be tissue-type specific and that synergism may depend on the histological origin of the cancer.