Highly active antiretroviral therapy (HAART) has suppressed viral replication and facilitated normalization of T cell subsets, resulting in restoration of immunity against opportunistic pathogens. Induction of full immune restoration in chronically infected individuals, including HIV-specific helper T cell responses, is considered a priority, particularly if immunological control of HIV is to be achieved. Regimens containing dual protease inhibitors (PIs) have provided greater suppression of viremia than single-PI regimens. We therefore conducted a prospective analysis of factors associated with immune restoration after 3 years of therapy in two cohorts of acutely and chronically HIV-infected patients, comparing dual- versus single-PI regimens. Earlier and more durable returns of p24-specific proliferation were demonstrated in patients receiving dual-PI compared with single-PI regimens. Individuals with restored p24 responses had larger reductions in total HIV-specific cytotoxic T lymphocytes (CTLs) associated with stronger viral suppression, but Gag-specific CTLs remained higher, demonstrating that Gag-specific helper T cell responses were a critical component of functional immune restoration. On examination of clinical factors associated with immune restoration, we demonstrated that decreasing activation of CD8+ T cells (%CD8+ CD38+) and increasing proportions of CD4+ T cells were independently associated with restoration of p24 responses. Minimal immune activation, resulting from maximal suppression of viral replication, was required for long-term restoration and maintenance of Gag-specific T cell responses. This study uniquely demonstrates that dual-PI regimens are superior in achieving these levels of virological control and immune restoration in both chronic and acute infection, compared with single-PI or non-PI regimens.