Background. Our objective was to compare the rate of viral rebound and therapy failure in patients receiving abacavir or efavirenz as the third drug ( in addition to 2 non-abacavir nucleosides) in combination antiretroviral therapy ( cART) and to compare the rate of metabolic alteration associated with these regimens. Methods. We conducted a multicohort prospective observational study of human immunodeficiency virus infected patients who had attained viral loads <= 80 copies/mL while receiving cART, without having previously received antiretrovirals. The rates of virological rebound, therapy failure, and lipid-level alteration during follow-up were calculated as the number of events divided by person-years of follow-up ( PYFU). A multivariable analysis was performed using a Poisson regression model. Results. We studied a total of 744 patients; the median age was 37 years, 27% of the patients were female, and 41% were heterosexual. There was a total of 854 PYFU spent receiving efavirenz and 285 spent receiving abacavir. The nucleoside reverse-transcriptase inhibitor pairs most frequently used were zidovudine/lamivudine ( 66% of PYFU), stavudine/lamivudine ( 17.6%), and stavudine/didanosine ( 5.4%). The adjusted relative rates of virological failure and therapy failure for abacavir, compared with those for efavirenz, were 2.17 ( 95% confidence interval [ CI], 1.12 - 4.18;) and 1.41 ( 95% CI, 1.01 - 2.01;), respectively. P = .02 P = .05 Conclusions. Patients with virological suppression while receiving regimens containing abacavir appear more likely to experience virological and therapy failure than those receiving efavirenz as their third drug. Although this is a selected group of adherent patients, bias cannot be ruled out, because this is a nonrandomized comparison.