Events that occur during acute HIV infection likely contribute to the immune dysfunction common in HIV-infected individuals. During this early stage, there is high-level viral replication, loss in CD4⁺ T cell number and function, and an up-regulation of proinflammatory and immunoregulatory cytokines. The mechanisms responsible for this are not completely understood. We hypothesize that the HIV envelope glycoprotein, gp120, contributes to immune dysfunction during early HIV infection. Using a cohort of subjects enrolled during acute and early HIV infection, we determined the amount of gp120, TNF-α, IL-6, IL-10, IFN-α, and IFN-γ in plasma at baseline and 6 months. At matched time points, we also measured CD4⁺ T cell proliferation, T cell activation, and apoptosis. Plasma from 109 subjects was screened for gp120. Thirty-six subjects (33%) had detectable gp120 (0.5–15.6 ng/ml). Subjects with greater than 1 ng/ml of gp120 at baseline had similar levels at all time points tested, even when viral replication was undetectable due to therapy. Subjects with detectable gp120 had higher levels of plasma IL-6, IL-10, and TNF-α. There was no difference in the level of T cell activation, proliferation, or apoptosis in subjects with gp120 compared to those without. We conclude that persistent expression of gp120 occurs in a subset of individuals. Furthermore, the presence of gp120 is associated with higher levels of plasma IL-6, IL-10, and TNF-α, which may contribute to immune dysfunction during early HIV infection.