Background and methods. The SMART study compared 2 strategies for using antiretroviral therapy - drug conservation (DC) and viral suppression (VS) - in 5472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/μL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported. Results. During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count <350 cells/μL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow-up with a CD4+ cell count <350 cells/μL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5-3.4]) for periods with the latest CD4+ cell count ≥350 cells/μL - an increase explained by the higher HIV RNA levels in the DC group. Conclusions. The higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death. Trial registration. Clinical Trials.gov identifier: NCT00027352. © 2008 by the Infectious Diseases Society of America. All rights reserved.