Phospholipase A2 (PLA2) extensively exists in various snake venom. Till now, a controversy remained to elucidate whether the PLA2 activity exclusively associates with the manifestation of the pharmacological activities. In the present study, we used liposome to imitate cell membrane for excluding the effects of receptor and membrane proteins, and estimating the molecular mechanism of snake venom phospholipase A2 on damaging liposome. Although a greater membrane damaging activity of Naja naja atra phospholipase A2 (NNA-PLA2) and notexin was noted in the presence of Ca2+, inhibitions of PLA2 activity by Sr2+ and Ba+2 were unable to abolish the membrane damaging effect. In addition, modification of Lys-82 and Lys-115 of notexin retained the full PLA2 activity, but the membrane damaging activity notably decreased. Fluorescence quenching studies, CD measurement, and tryptophan fluorescence lifetime assay indicated that liposome induced the £\-helix conformation change and the tryptophan residues microenviroment change with the addition of Ca2+, Sr2+ or EDTA. Rhodamine quenching assay revealed that NNA-PLA2 and notexin formed oligomers when they bound with liposome. Besides, the modified PLA2 (BPB-PLA2) only formed monomer when it bound with liposome and lost the membrane damaging activity. Taken together, these results indicate that the membrane damaging effects of NNA-PLA2 and notexin are not critically caused by their enzymatic activitys and are probably associated with oligomerization.