Both naive and memory T lymphocyte responses are lost during advanced HIV infection. Treatment with highly active antiretroviral therapy (HAART) is associated with an increase in T lymphocytes and a reduction in viral load. However, the viral response to HAART in patients with low levels of helper T lymphocytes and a high viral load is often not satisfactory. We investigated the capacity of long-term HAART to reconstitute the immune system in severely ill patients. A nonselected longitudinal patient population with high baseline viral levels and CD4(+) cells below 100 x 10(6)/liter were monitored for 2 years during HAART. Markers to estimate the therapeutic effects included viral levels and cell surface markers representing naive and memory T lymphocytes as well as activation markers, B cells, NK cells, and clinical events. After 2 years of treatment, viral load was reduced to undetectable levels in 55% (viral responders, vRs) and less than 1 log (median value) from baseline in 45% (viral low responders, vLRs). Elevated numbers of memory and naive CD4(+) and CD8(+) cells as well as a decrease in activation markers were seen in both vRs and vLRs. However, the magnitude was greater in vRs. No differences in the clinical outcome were observed between vRs and vLRs. We conclude that most patients, even in advanced stages of HIV disease, benefited from HAART. The magnitude of the response was related to good viral reduction, but even patients with poor viral reduction had a recovery of naive and memory CD4(+) and CD8(+) cells. Even a small reduction in viral load is thus of importance for health and potentially also for years of survival.