BACKGROUND: Highly active antiretroviral therapy (HAART) may fail, especially in pre-treated patients. OBJECTIVE: To examine retrospectively whether heavily pre-treated patients not responding to HAART at least once respond to a salvage therapy with abacavir, a nucleoside reverse transcriptase inhibitor (NRTI) plus a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) and one or two protease inhibitors (PI). PATIENTS: We retrospectively identified and analysed patients followed in the Swiss HIV Cohort Study with > 1000 HIV RNA copies/ml on HAART, naive to abacavir who were switched to abacavir plus one NNRTI (efavirenz or nevirapine) and one or two PI which had not been used in the previous HAART. RESULTS: Of 23 identified HIV-infected patients with four (median) therapy changes before salvage, 10 patients (43%) achieved a decrease of plasma HIV RNA > 0.5 log10 at 6 months of therapy. After 6 months only two patients had an HIV-1 RNA < 500 copies/ml, one of them < 50 copies/ml. Seven patients increased their CD4 cell counts by > 30% above baseline. Three patients, all with CD4 cell counts < 100 x 10(6)/l before salvage therapy had a > 30% decline in CD4 cell count. An extended number of resistance-associated mutations was found in almost all patients at baseline. One patient had two new AIDS-defining events. Five patients (22%) discontinued treatment because of side-effects, mainly occurrence of a rash. CONCLUSION: Salvage therapy in intensively pre-treated patients has a low virological success rate despite usage of abacavir and NNRTI. Nevertheless, this did not correlate with immunological and clinical course. This study emphasizes the difficulty of second-line treatment in HIV-1 infection and stresses the need for new compounds.