A three-dimensional quantitative structure-activity relationship (QSAR) using steric and electrostatic fields (comparative molecular field analysis, CoMFA) applied to 36 aryl sulfonamides assayed for endothelin receptor subtype-A (ETA) antagonism provided high cross-validation correlations (0.7) and showed promising predictive ability. The results were validated through trials using scrambled activities as well as trials using scrambled orientation of molecules. CoMFA was used to discriminate between alternate hypothetical biologically active conformations. CoMFA was also used to discriminate between two different molecular superpositions representing possible positioning within the receptor binding site. The preferred superposition supports hypotheses that suggest Tyr129 in the ETA receptor as a key residue for antagonist binding. Significant CoMFA results were obtained when crudely optimized geometries and simple charge schemes were used. The results improved on refinement, most substantially with refinement of the atomic charges.