Objectives: To examine risk factors for sub-optimal CD4 recovery on suppressive highly active antiretroviral therapy (HAART) and assess long-term clinical and immunological outcomes. Methods: Retrospective analysis of 286 HIV-positive patients from a university clinic who initiated HAART with CD4 count <350 cells/μL between January 1996 and July 2006 and achieved ≥52 weeks of viral suppression (VS). Sub-optimal and optimal CD4 count recovery were defined by gains of <150 and ≥150 cells/μL during the first year of VS, respectively. Risk factors were analysed by multivariate logistic regression and markers of immune maturation and activation were evaluated prospectively for a sub-group of patients with prolonged (>5 years) VS. Results: One hundred and two (36%) patients had sub-optimal CD4 recovery. Male gender, lower pre-HAART viral load, HAART toxicity and use of opportunistic infection (OI) prophylaxis were independent risk factors on multivariate analysis (P < 0.05). Outcomes of duration of VS on HAART (4 years), new OI events (1%) and mortality (5%) were similar between groups. Markers of immune maturation and activation were higher among patients with sub-optimal CD4 recovery (P < 0.05). Conclusions: Among HIV-positive patients with long-term VS, sub-optimal CD4 recovery was common but morbidity and mortality remained low. In addition, persistent CD4 T-cell activation appeared to blunt long-term CD4 gains. © 2009 British HIV Association.