3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) has been used to elucidate the atomic details of the RT/TT interactions and to identify the most important features impacting the TT antiretroviral activity. Two 3D-QSAR CoMFA and CoMSIA models were derived, using the TT pEC?? values measured against wild-type (WT) HIV-1 (model A) and the Y188L mutant form (model B), respectively, as the dependent variable. The final model A CoMSIA (rncv² = 0.97, rcv² = 0.89, SEE = 0.314, and rpred² = 0.82) and model B CoMSIA (rncv² = 0.91, rcv² = 0.61, SEE = 0.236, and rcv² = 0.73) analyses were more predictive. The results allowed us to obtain useful information for the design of new compounds with improved potency towards WT HIV-1 or that are potentially active against the Y188L mutant.