To evaluate factors associated with durable viral suppression (DVS), low viral rebound (virus load of 500-5000 copies/mL), and high viral rebound (virus load above 5000 copies/mL), we studied 3736 patients who achieved an undetectable virus load (i.e., <500 copies/mL) while receiving an initial highly active antiretroviral therapy regimen containing a protease inhibitor (PI). A total of 2636 patients (71%) had DVS, 387 (10%) had low viral rebound, and 713 (19%) had high viral rebound. Factors associated with DVS were antiretroviral-naive status, choice of PI (indinavir or boosted PI), lower virus load and higher CD4+ cell count, shorter duration of therapy (<6 months), and larger CD4+ cell increment until an undetectable virus load was attained. These factors (except for receipt of indinavir) were also associated with low versus high viral rebound. Compared with patients with DVS, patients with high viral rebound were more likely to experience clinical failure (adjusted hazard ratio [aHR], 1.71; 95% confidence interval [CI], 0.97-3.02) and immunologic failure (aHR, 1.57; 95% CI, 1.34-1.83), and patients with low viral rebound were as likely to experience these types of failure (aHR for clinical failure, 1.18 [95% CI, 0.48-2.92]; aHR for immunologic failure, 1.07 [95% CI, 0.87-1.32]), suggesting that a low viral rebound while receiving HAART that contains a PI has no significant consequence on midterm clinical outcome.