This systematic review summarises the evidence for treatment efficacy and tolerability of highly active antiretroviral therapies containing two nucleoside reverse transcriptase inhibitors (NRTI) with a protease inhibitor (PI), compared with two NRTIs alone for the treatment of HIV-1 infection in randomised controlled trials. Three electronic databases (Medline, Embase, and the Cochrane Library) were searched up to December 2003. 16 randomised controlled trials met the inclusion criteria and were included in the analysis from 328 articles screened. The pooled analysis indicated that treatment with two NRTIs with a PI is more effective in achieving viral suppression than two NRTIs alone (relative risk [RR] 3.44, 95% confidence interval [CI] 2.43-4.87). However, the RR for discontinuation of treatment due to adverse events of treatment with two NRTIs with a PI compared with two NRTIs alone was 1.81 (95% CI 1.17-2.79). The benefits of treatment with two NRTIs and a PI are substantial among those who can tolerate the regimen in comparison with treatment with two NRTIs alone.