A series of 3,5-benzylidene-4-piperidones, -, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. The bioevaluation of - was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θ and θ and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, - were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. A positive correlation was noted between the interplanar angle θ of one of the aryl rings and the adjacent olefinic linkage with IC values in the Molt4/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (π) value of the aryl substituents and the IC values of the compounds towards the Molt4/C8 and CEM cells. The dienones in series demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents.