Potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type were docked into nine NNRTIs binding pockets of HIV-1 reverse transcriptase (RT) structures. The docking results indicate that pyridinone analogues adopt a butterfly conformation and share the same binding mode as the crystal inhibitors in the pocket geometries of nevirapine, 1051U91, 9-Cl-TIBO, Cl-alpha-APA, efavirenz, UC-781, and S-1153. The results are in agreement with the data concerning mutational and structure-activity relationships available for pyridinone analogues and aid in the understanding, at the molecular level, of the biological response of published hybrid pyridinone molecules. Strategies to design further pyridinone derivatives active against RT containing mutations are discussed.