PM3 semiempirical molecular orbital calculations were applied to compare the reactivity of 2-cephems and 3-cephems. For 2-cephems it is evident that, as the alkyl groups at the 4-position increase in size, the stereoisomers having 4β-carboxy groups are more reactive toward an incoming nuclcophile than those having 4α-carboxy groups. The calculated results also imply that 3-cephems are more reactive than 2-cephems upon reactions with an incoming nucleophile.