The benzophenanthridine alkaloid sanguinarine has antimicrobial and possibly anticancer properties but it is not clear to what extent these activities involve DNA damage. Thus, we studied its ability to cause DNA single and double strand breaks, as well as increased levels of 8-oxodeoxyguanosine, in human colon cancer cells and found DNA damage consistent with oxidation. Since the tumor suppressor p53 is frequently involved in inducing apoptosis following DNA damage we investigated the effect of sanguinarine in wild type, p53-mutant and p53-null colon cancer cell lines. We found them to be equally sensitive to this plant compound, indicating that cell death is not mediated by p53 in this case. In addition, our observation that apoptosis induced by sanguinarine is initiated very rapidly raised the question whether there is enough time for cellular signaling in response to DNA damage. Moreover, the abundance of double strand breaks is not consistent with only oxidative damage to DNA. We conclude that the majority of DNA double strand breaks in sanguinarine-treated cells are likely the result, rather than the cause, of apoptotic cell death and that apoptosis induced by sanguinarine is independent of p53 and most likely independent of DNA damage.