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To assess the resistance profile of tipranavir.Resistance analyses were performed on Boëhringer Ingelheim-sponsored studies examining the safety and efficacy of tipranavir in highly treatment-experienced individuals at 24 weeks. Virologic response rates based on the presence of baseline primary protease inhibitor mutations and based on baseline tipranavir susceptibility were evaluated, and the development of protease mutations during treatment with tipranavir was analyzed.Virologic response rates in tipranavir-treated individuals were reduced when isolates with substitutions at amino acid positions I13, V32, M36, I47, Q58, D60 V82 or I84 were present at baseline. In addition, virologic response rates to tipranavir decreased when the number of baseline protease inhibitor (PI) mutations was five or more. Individuals who received tipranavir without concomitant enfurvitide and had five or more baseline PI mutations group began to lose antiviral response between weeks 4 and 8. However, individuals taking enfuvirtide with tipranavir were able to achieve greater than 1.5 log10 reductions in viral load from baseline out to 24 weeks even if they had five or more baseline PI mutations. Virologic response rates to tipranavir decreased when the baseline phenotype for tipranavir had a greater than three-fold shift in the 50% effective concentration (EC50) from reference. The most common protease mutations that developed in tipranavir-treated individuals who experienced virologic failure were L10I/V/S, I13V, L33V/I/F, M36V/I/L V82T, V82L, and I84V. The resistance profile in treatment-naive individuals was not characterized.Baseline genotypic and phenotypic data provide valuable information on the likelihood of a virologic response to tipranavir.