ABSTRACT Antiretroviral-treated human immunodeficiency virus (HIV) type 1-seropositive individuals can remain clinically stable for a long period of time with an increasing CD4 cell count irrespective of incomplete viral suppression. We evaluated the role of neutralizing antibody (NtAb) activity in the etiopathogenesis of this viro-immunological disconnection (defined as an increasing CD4 ⁺ -cell count despite a persistent, detectable viral load during antiretroviral therapy) in 33 patients failing therapy with two analogue nucleoside reverse transcriptase inhibitors. An HIV NtAb titer of ≥1:25 was detected in specimens from 16 out of 33 (48%) patients. A significant correlation was found between NtAb titers and CD4 ⁺ -cell counts ( P = 0.001; r = 0.546) but not with HIV RNA levels in plasma. Five patients with a viro-immunological disconnection had an NtAb titer of >1:125, statistically higher than the NtAb titers for the remaining 28 patients with both virologic and immunologic failure ( P < 0.0001). The HIV-specific humoral immune response could play a role during antiretroviral treatment to improve immunological function despite an incomplete suppression of viral load.