The pro-apoptotic ability of (Z)-3,5,4'-Tri-O-methyl-resveratrol (R3) was investigated in vitro on the human lymphoblastoid cell line TK6 and its p53-knockout counterpart (NH32). In both cell lines, R3 induced the stimulation of caspase-3. Although R3 induced growth inhibition and apoptosis of both cell lines, two distinct mechanisms were observed. The p53-knockout NH32 cells were shown to override the G2/M phase checkpoint with development of hyperdiploid cells, whereas TK6 cells accumulated at G2/M. As p53 function is often altered in human cancer cells, these results show that the pro-apototic effects of R3 against tumor cells are independent of their p53 status.