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To characterize immune phenotype and thymic function in HIV-1-infected adults with excellent virologic and poor immunologic responses to highly active antiretroviral therapy (HAART).Cross-sectional study of patients with CD4 T cell rises of ≥ 200 × 106 cells/l (CD4 responders; n = 10) or < 100 × 106 cells/l (poor responders; n = 12) in the first year of therapy.Poor responders were older than CD4 responders (46 versus 38 years;P < 0.01) and, before HAART, had higher CD4 cell counts (170 versus 35 × 106 cells/l;P = 0.11) and CD8 cell counts (780 versus 536 × 106 cells/l ; P = 0.02). After a median of 160 weeks of therapy, CD4 responders had more circulating naive phenotype (CD45+CD62L+) CD4 cells (227 versus 44 × 106 cells/l ; P = 0.001) and naive phenotype CD8 cells (487 versus 174 × 106 cells/l ; P = 0.004) than did poor responders (after 130 weeks). Computed tomographic scans showed minimal thymic tissue in 11/12 poor responders and abundant tissue in 7/10 responders (P = 0.006). Poor responders had fewer CD4 cells containing T cell receptor excision circles (TREC) compared with CD4 responders (2.12 versus 27.5 × 106 cells/l ; P = 0.004) and had shorter telomeres in CD4 cells (3.8 versus 5.3 kb ; P = 0.05). Metabolic labeling studies with deuterated glucose indicated that the lower frequency of TREC-containing lymphocytes in poor responders was not caused by accelerated proliferation kinetics.Poor CD4 T cell increases observed in some patients with good virologic response to HAART may be caused by failure of thymic T cell production.