Rapid recovery of CD4⁺ T cells after intensive chemotherapy is limited by an age-dependent decline in thymopoiesis. Here we sought to determine whether similar limitations exist for CD8⁺ T-cell regeneration. After intensive chemotherapy, CD8⁺ T cells had a faster effective doubling time than CD4⁺ T cells (median, 12.6 v 28.2 days, P < .05). Accordingly, at 3 months posttherapy, mean CD8⁺ T-cell number had returned to baseline, whereas mean CD4⁺ T-cell number was only 35% of pretherapy values (P < .05). These differences were primarily due to very rapid expansion of CD8⁺CD57⁺ and CD8⁺CD28⁻ subsets. At 3 months posttherapy, there was no relationship between age and CD8⁺ T-cell number (R = −.02), whereas CD4⁺ T-cell number was inversely related to age (R = −.66) and there were no discernible differences in CD8⁺ recovery among patients with or without thymic enlargement, whereas CD4⁺ recovery was enhanced in patients with thymic enlargement after chemotherapy (P < .01). Therefore thymic-independent pathways of T-cell regeneration appear to rapidly regenerate substantial numbers of CD8⁺, but not CD4⁺ T cells, resulting in prolonged T-cell subset imbalance after T-cell depletion. These inherent distinctions between CD4⁺v CD8⁺ T-cell regeneration may have significant implications for immunotherapeutic strategies undertaken to eradicate minimal residual neoplastic disease after cytoreductive chemotherapy.