Aim To compare the machenisms of the signal pathways between the TNFα-and oridonin-induced L929 cell death. Methods MTT,Hoechst 33258 fluorescence staining, DNA agarose gel electrophoresis and Western blot analysis were used. Results Unlike oridonin, which induced atypical apoptosis in L929 cells with IC_ 50 (24.8±1.2) μmol·L~ -1 , TNFα induced typical apoptosis with IC_ 50 (20.9±1.9) μg·L~ -1 . Oridonin and TNFα initiated apoptotic morphologic changes, however, DNA fragmentation was not found in oridonin-treated cells, but was found in TNFα-treated L929 cells; caspase-3 inhibitor (z-DEVD-fmk), caspae-8 inhibitor (z-IETD-fmk) and Pan-caspase inhibitor (z-VAD-fmk) augmented oridonin- and TNFα-induced cell death, however, caspase-9 inhibitor (z-LEHD-fmk) augmented only oridonin-induced L929 cell death; ERK inhibitor (PD98059) effectively suppressed oridonin- and TNFα-induced L929 cell death, whereas, p38 inhibitor (SB203580) only inhibited TNFα-induced L929 cell death; In addition, oridonin augmented endogenous pro-TNFα expression and IκB phosphorylation. Conclusion Oridonin up-regulated TNFα expression through activation of the transcription factor NF-κB, and induced L929 cell death partially through TNFα signal pathways.