The NHS is a prospective, multicenter, observational study of HIV-infected active duty military personnel and beneficiaries from the Army, Navy/Marines, and Air Force. In 1119 patients with documented estimated date of seroconversion, markers indicative of immune activation, dysfunction, and responsiveness were determined in those who achieved virologic suppression with antiretroviral therapy. Responses to hepatitis B virus (HBV) vaccine, an indicator of in vivo immune function, were also assessed. The timing of antiretroviral therapy was indexed to the estimated dates of seroconversion and/or entry into the cohort. Normal value of the CD4+ counts were evaluated from the HIV-1-uninfected population. The median CD4+ count in this population was approximately 900 cells/μL and was considered as a therapeutic target for HIV-infected persons receiving antiretroviral therapy. Among the 1119 HIV-1-infected participants, CD4+ normalization was achieved in 38.4% vs 28.3% of those initiating ART within 12 months versus after 12 months from the estimated dates of serconversion (p=0.001). Incrementally higher CD4+ recovery (<500, 500-899, and ≥900 cells/μL) was associated with stepwise decreases in AIDS risk and reversion of markers of immune activation, dysfunction, and responsiveness to levels approximating those found in HIV-1-uninfected persons. Participants with CD4+ counts of 500 cells/μL or higher at study entry (adjusted odds ratio, 2.00; 95% CI, 1.51-2.64; p<0.001) or antiretroviral therapy initiation (aOR, 4.08; 95% CI, 3.14-5.30; p<0.001) had significantly increased CD4 normalization rates compared with other participants. However, even among individuals with a CD4+ count of 500 cells/μL or higher at both study entry and before antiretroviral therapy, the odds of CD4+ normalization were 80% lower in those initiating antiretroviral therapy after 12 months from the estimated dates of seroconversion and study entry (aOR, 0.20; 95% CI, 0.07-0.53; p=0.001). Initiation of antiretroviral therapy within 12 months of estimated dates of serconversion versus later was associated with a significantly lower risk of AIDS (7.8% versus 15.3%; p=0.002), reduced T-cell activation (percent CD4+ HLA-DR+ effector memory T cells, 12.0% versus 15.6%; p=0.03), and increased responsiveness to HBV vaccine (67.9% versus 50.9%; p=0.07). In conclusion, deferral of antiretroviral therapy beyond 12 months of the estimated dates of seroconversion diminishes the likelihood of restoring immunologic health in HIV-1-infected individuals.