OBJECTIVES: Higher plasma CD4 cell counts per mm at ART initiation (AI-CD4) improve long-term CD4 responses and survival. Recent data suggest CD4 > 750 is a clinically significant threshold for AIDS-related illness reduction and immune “normalization”.  We evaluated the effect of AI-CD4 on  achieving CD4 >750 and mortality risk. METHODS: Among HIV Outpatient Study patients seen during 1996-2012 for three or more years after AI, we analyzed CD4 trajectories and mortality rates per 100 persons-years (MR) by AI-CD4, and the association of AI-CD4 with achieving CD4 >750 (“normalization”) using Kaplan-Meier methods and Cox proportional hazards models. RESULTS: Of 1327 eligible patients followed a median of 7.9 years, > 85% received HAART ≥ 75% of follow-up time, and 64 died. Higher AI-CD4 was associated with increased median peak CD4 (p < 0.001).  Maximal CD4 response and benefit plateaued at eight years, but differences by AI-CD4 persisted (p < 0.001).  Lower crude MRs (p = 0.005) and higher CD4 closest to death (p = 0.013) were associated with higher AI-CD4.  Increases in median CD4 for persons with AI-CD4 < 50 and 50-199 converged by eight years (< 50% achieved CD4 > 750) whereas patients with AI-CD4 > 350 normalized by eight years (> 80% of patients). In multivariable analyses, higher AI-CD4 was the only factor independently associated with achieving CD4 normalization during follow-up.  CONCLUSIONS: Progressively higher AI-CD4 predicted greater long-term CD4 gains, achieving CD4 normalization, increased crude survival rates, and higher CD4 at death. CD4 gains and chances of reaching CD4 normalization peaked at eight years after AI.  Most with AI-CD4 >350 eventually achieved CD4 normalization while less than half with AI-CD4s < 50 and 50-199 did. AI-CD4 ≥ 500 optimized the likelihood of CD4 normalization confirming the hazards of delayed and support AI at CD4 ≥ 500.