Background. The SMART study randomized 5472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/μL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral supression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/μL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART. Methods. Patients who were either ART naive (n = 249) or who had not been receiving ART for ≤6 months (n = 228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii). Results. A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for ≤6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for ≤6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; P = .02); outcome (ii), 3.26 (95% CI, 1.04-10.25; P = .04); outcome (iii), 7.02 (95% CI, 1.57-31.38; P = .01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; P = .002). Conclusions. Initiation of ART at CD4+ cell counts >350 cells/μL compared with <250 cells/μL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial. Trial registration. ClinicalTrials.gov identifier: NCT00027352.