AbstractMolecular Orbital (MO) indices were computed (CNDO/2) for three series of sulfonamide carbonic anhydrase inhibitors, in their neutral and anionic forms.Linear regression analyses between the calculated indices and both physico‐chemical and enzyme inhibition data provide good correlations which enable us to test the predictive and diagnostic aspects of the quantitative structure‐activity relationships employing quantum chemical indices.In particular:a)The molecular size affects the inhibitory power among the different sulfonamide derivatives (aliphatic, arylic and bridged diarylic) but not significantly within each molecular series;b)the MO indices are good predictors of the various experimental molecular properties and suggest that the less electron‐rich the sulfamoyl group is, the more favoured are both the hydrophobic and hydrophilic steps leading to enzyme inhib