1,3,4,5-tetrasubstituted-pyrazoles (TPs) have been recently identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies, followed by docking-based comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), has been used to elucidate the atomic details of the RT/TP interactions and to identify the most important features impacting the TP antiretroviral activity. The final CoMSIA model resulted to be the more predictive, showing r (ncv) (2) = 0.97, r (cv) (2) = 0.723, SEE = 0.248, F = 240.291, and r(2) (pred) = 0.77. The results allowed us to obtain useful information for the design of new compounds with improved potency toward WT HIV-1 and also against clinically relevant resistant mutants.