The long-term immunological efficacy of regimens including lopinavir/ritonavir (LPV/r) has not been assessed in HIV-infected HAART-experienced subjects. The present study included 452 consecutive HIV-infected outpatients starting LPV/r before May 2003 after failing (HIV-RNA > 1000 copies/ml) HAART. Four groups were considered according to CD4 cell counts at LPV/r initiation: group 1 (G1, n = 115) < 100 cells/mm(3); group 2 (G2, n = 113) 100-199 cells/mm(3); group 3 (G3, n = 115) 200-349 cells/mm(3); group 4 (G4, n = 109) >/= 350 cells/mm(3). The majority of patients were males (n = 320, 70.8%), the median age was 38 years, and 180 (39.6%) were on CDC stage C. The median time of previous HAART was 51.1 months (12-81.7) and a median of 7 antiretroviral regimens and of 3 protease inhibitors was changed before LPV/r. The mean CD4 cell count increase was 105, 113, 128, and 144 cells/mm(3) after 12 months (p < 0.01 for each group) and 128, 106, 90, and 100 cells/mm(3) at month 48 (p < 0.01 for each group) in G1, G2, G3, and G4, respectively. The mean increase was comparable among the four groups. The on treatment analysis showed a better immunologic response among G1 and G2 patients from month 36. Forty-seven patients (10.4%), mainly in G1 and G2, maintained LPV/r despite persistent HIV-RNA > 1000 copies/ml. A mean increase of 64 and 65 cells/mm(3) and of 88 and 56 cells/mm(3) at month 12 and 48 was observed in G1 and G2, respectively. The use of LPV/r-based regimens also provided a durable immunologic recovery in highly pretreated HIV-infected subjects.