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This longitudinal natural history study aimed to assess the pattern and durability of neurocognitive benefits of progressively more potent combination antiretroviral therapy in HIV-1 infection. A cohort of 141 homosexual or bisexual men were assessed semiannually for CD4 count, HIV RNA viral load, medical and depressive symptoms, and a neuropsychological test battery, including psychomotor speed, verbal memory, and executive function. In a mixed-effects model, increasingly potent antiretroviral therapy was associated with improvement in tests of psychomotor processing speed. This study contributes to the growing literature documenting the longitudinal benefit provided by potent antiretroviral therapy for neuropsychological function, particularly psychomotor processing speed, in patients with HIV illness.