Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of carbonic anhydrase inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The large set of 37 different aromatic/heterocyclic sulfonamides carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as CA II chosen for the present study. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q(2) values 0.538 and 0.527 and r(2) values 0.974 and 0.971 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. The predicted r(2) values are 0.565 and 0.502 for CoMFA and CoMSIA, respectively. Results indicate that the CoMFA and CoMSIA models could be reliable model which may be used in the design of novel carbonic anhydrase inhibitors as leads.