The correlation between the cytotoxicity of seven vitamin K2 (menaquinone) derivatives and thirteen chemical descriptors determined by CONFLEX5/CAChe Worksystem 4.9 (PM3) was investigated. After determination of the conformation of the seven vitamin K2 derivatives and approximation to the molecular form present in vivo (biomimetic) by CONFLEX5, the most stable structure was then determined by CAChe Worksystem 4.9 MOPAC (PM3). The vitamin K2 derivatives with one to three isoprenyl units [1-3] showed an extended form, whereas those with four to seven isoprenyl units [4-7] displayed a spherical form. The human hepatocellular carcinoma HepG2 cells displayed a good correlation between cytotoxicity and all the descriptors except for the electron affinity and lowest unoccupied molecular orbital energy (E(LUMO)). The absolute hardness (eta)--absolute electron negativity (chi) activity diagram determined by this calculation method may be useful for estimating the cytotoxic activity of vitamin K2 derivatives against HepG2 cells. The human squamous cell carcinoma HSC-2 and HSC-3 cells showed similar correlation. The human promyleocytic leukemia HL-60 cells showed the good correlation between cytotoxicity and molecular length. The present study demonstrates for the first time the best correlation between cytotoxic activity and molecular shape or molecular weight of vitamin K2 derivatives, regardless of the type of target cells.