Molecular modeling of a series of HIV reverse transcriptase (RT) non-nucleoside inhibitors (2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners) was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Docking simulations were employed to position the inhibitors into RT active site to determine the most probable binding mode and most reliable conformations. The study was conducted using a complex receptor-based and ligand-based alignment procedure and different alignment modes were studied to obtain highly reliable and predictive CoMFA and CoMSIA models with cross-validated q(2) value of 0.723 and 0.760, respectively. Furthermore, the CoMFA and CoMSIA contour maps with the 3D structure of the target (the binding site of RT) inlaid were obtained to better understand the interaction between the RT protein and the inhibitors and the structural requirements for inhibitory activity against HIV-1. We show that for 2-amino-6-arylsulfonylbenzonitriles inhibitors to have appreciable inhibitory activity, bulky and hydrophobic groups in 3- and 5-position of the B ring are required. Moreover, H-bond donor groups in 2-position of the A ring to build up H-bonding with the Lys101 residue of the RT protein are also favorable to activity.