Defects in apoptotic machinery vary among individual cancer cells, and the efficacy of chemotherapy in killing cancer cells depends on the successful induction of apoptosis. This study tested the hypothesis that the intrinsic ability of a cancer cell's natural resistance to apoptosis would indicate its ability in resistance to chemotherapy. Four widely studied human colorectal cancer cell lines, SW480, HT-29, LoVo and Caco-2, were examined for their apoptotic fates in spontaneous cultures for up to 6 days using flowcytometry. Chemoresponse of these cells was tested against anti-colorectal cancer drugs 5-fluorouracil (5-FU) and oxaliplatin (OXP) at different peak plasma concentrations (PPCs) using MTT assay. Apoptosis analyses demonstrated that, from Day 2 to Day 6 in spontaneous cultures, SW480 and HT-29 lines showed resistance to apoptosis by having much less average early and late apoptotic cells than LoVo and Caco-2 lines with differences of 3.2- to 5.2-fold. Interestingly, apoptosis-resistant SW480 and HT-29 exhibited higher chemoresistance to both 5-FU (P < 0.01 at 5×, 10×, and 50× PPC) and OXP (P < 0.01 at 5× and 10× PPC, and P < 0.05 at 50× PPC) than LoVo and Caco-2. Colorectal cancer cells' natural resistance to apoptosis is an intrinsic ability that correlates with resistance to chemotherapeutic drugs 5-FU and OXP. Cancer cells' natural apoptotic phenotypes may help predict the outcome of chemotherapy in colorectal cancers.