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Tipranavir (TPV) and darunavir (DRV) are potent against protease inhibitor (PI)-resistant viruses. Efficacy of these compounds when confronting distinct HIV subtypes is not known.All clinical specimens from HIV-positive patients sent to our institution for drug resistance testing between 1999 and 2006 were analysed. The prevalence of TPV and DRV resistance mutations was assessed based on the latest International AIDS Society-USA panel list. Phenotypic susceptibility to DRV and TPV was examined in a subset of these samples using the PhenoSense assay.A total of 1364 genotypes were analysed, including 1178 from individuals infected with clade B (285 drug naive) and 186 with non-B subtypes (137 drug naive). The mean number (±SD) of DRV resistance-associated mutations was higher in clade B than non-B (0.4 ± 0.9 versus 0.06 ± 0.3; P < 0.001), and more frequent among PI-experienced than drug-naive patients (0.6 ± 1.02 versus 0.02 ± 0.21; P < 0.001). In contrast, the mean number of TPV resistance-associated mutations was higher in non-B than B subtypes (2.7 ± 1 versus 1.2 ± 1.6; P < 0.001), regardless of PI experience. Susceptibility to TPV and DRV was examined in 29 drug-naive patients infected with non-B subtypes (1A, 3C, 2CRF01_AE, 9CRF02_AG, 1CRF12_BF, 3CRF14_BG, 3F and 7G). All showed susceptibility to DRV and 93% to TPV. Interestingly, two subtype F specimens showed reduced TPV susceptibility, with fold-changes of 2.7 and 2.1, respectively.Non-B subtypes show a greater number of TPV resistance-associated mutations than B viruses, regardless of PI exposure. While HIV clade has no influence on DRV susceptibility, some F subtypes may show reduced TPV susceptibility.