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Background: Colorectal cancer is a leading cause of mortality worldwide. Resistance of this cancer to the available chemotherapeutic agents creates a need to develop new therapeutic agents. Pentoxifylline (PTX) has been shown to have anticancer effects on multiple cancer types. Objective: In this study, we evaluated the anticancer effect of PTX in CRC cells. Methods: We measured PTX's effect on cell proliferation using the MTT assay and on cell death induction by PI staining/flowcytometry. We also assessed the effect of treatment on mitochondrial membrane potential (MMP). Results: We found that PTX arrested the growth SW480 CRC cells with a peak effect plateauing at 10 mM of PTX after 72 h of treatment. Surprisingly, similar effect wasn't noticed in HCT-116 cells. Similar pattern of effect was noticed on apoptosis of both cell lines, as PTX induced more apoptosis on SW480 cells with no similar effect on HCT-116 cells. Studies using variable caspase inhibitors showed involvement of primarily capsase-9, as well as caspases-2 and -3 but not capsase-8. PTX also induced MMP changes leading to caspase-dependent apoptotic cell death. In addition to that, results indicated that apoptosis was caspase-dependent and was mediated through the mitochondria. Conclusion: These findings indicate that PTX has a promising antitumor activity against CRC cells and warrants further clinical evaluation.