Two alkaloids, evodiamine and rutaecarpine, isolated from the dried fruits of Evodia rutaecarpa Bentham were evaluated in vitro for antiproliferation activity on tumor cells versus human peripheral blood mononuclear cells (PBMC). Evodiamine had more potent cytotoxic effects on five tumor cell lines (human malignant melanoma A375-S2, human cervical cancer HeLa, human breast adenocarcinoma MCF7, human acute monocytic leukemia THP-1, murine fibrosarcoma L929) than rutaecarpine. Moreover, evodiamine did not affect PBMC viability for a 36 h culture period. Although apoptotic bodies were observed in evodiamine-treated L929 cells stained with Hoechst 33258, DNA fragmentation as a hallmark of apoptosis was not found. Caspases were involved in the protection of L929 cells against cell death. Evodiamine initiated atypical apoptosis in L929 cells by cycle arrest at the G0/G1 phase.