To analyze factors associated with long-term (>or=2 years) suppression of virus load (VL), we performed a nested case-control analysis of 1235 Human Immunodeficiency Virus Outpatient Study cohort participants who were well characterized by multiple VL and CD4(+) cell count determinations. Of these patients, 286 (23.1%) had maintained undetectable VLs (i.e., <400 copies/mm(3) or <50 copies/mm(3)) for >or=2 years. Being treatment naive at the start of antiretroviral therapy was associated with a greater likelihood of achieving long-term suppression of VL (odds ratio [OR], 1.5; 95% confidence interval, 1.0-2.0; P=.028). In multivariate models, abacavir, indinavir, efavirenz, and drug combinations that included both lamivudine and indinavir were the most effective treatments for achieving long-term suppression of VL (adjusted OR for each, >3.6; P value for each, <.01). Long-term suppression of VL is more likely in treatment-naive than in treatment-experienced patients, but there were several drugs--abacavir, efavirenz, indinavir, and drug combinations including lamivudine and indinavir--that appeared to be effective, whether they were part of a first or subsequent drug regimen.