A semiempirical molecular-orbital method (CAChe) was applied to delineate the relationship between the cytotoxicity (evaluated by 50% cytotoxic concentration, CC50) of fifteen phenoxazine derivatives and eleven physical parameters (descriptors). Most of the phenoxazine derivatives had extended and planar structure. The cytotoxic activity of phenoxazines against the human oral squamous cell carcinoma HSC-2 and HSC-4 cells correlated to electron affinity, absolute hardness (eta), absolute electron negativity (chi) and octanol-water distribution coefficient (log-P). However, only log-P was correlated to CC50 in the HSC-3 cells, whereas only heat of formation and log-P were correlated to CC50 in the human promyelocytic leukemia HL-60 cells. The cytotoxic activity of the phenoxazine derivatives became maximum at the log-P = 5.9. Their cytotoxicity strongly depended on the chi value, but not on the eta value. Compounds with relatively higher cytotoxicity showed higher chi value (chi > 5.28), whereas compounds with relatively lower cytotoxicity showed lower chi value (chi < 4.27). These data suggest that appropriate chemical descriptors should be selected to estimate the cytotoxicity of phenoxazines, depending on the target cells.