The efficacy of two-class versus three-class antiretroviral salvage treatment was analyzed retrospectively in 63 HIV-infected patients in whom highly active antiretroviral therapy failed. Twenty-eight patients (group A) received two-class therapy, and 35 patients (group B) received three-class therapy. After 3 months of treatment, a significantly greater proportion of patients in group B (23/35, 65.7%) than in group A (8/28, 28.5%) showed a > or = 1 log10 decrease in the plasma HIV RNA level (P = 0.0034). However, after 9-12 months, 12 of 23 (52.1%) group B responders showed viral load rebound. The results were partially explained by the finding that, at baseline, the great majority (21/27, 77.7%) of group A patients showed mutations conferring resistance to all drugs administered, whereas in group B patients' susceptibility to at least two drug classes was retained. However, after 9-12 months of therapy, most (18/20, 90%) of the short-term responders in group B showed emergence of additional mutations that hampered long-term response.