Sixteen HIV-1 seropositive individuals participated in a single-blind, placebo-controlled, crossover-design study of the effectiveness of 30 mg/ day of methylphenidate (MPH) in the treatment of HIV-associated cognitive slowing. Regression analyses revealed that participants who entered the study with a greater degree of either depressive symptomatology or cognitive slowing tended to demonstrate a better response to MPH on computerized measures of choice and dual-task reaction time. Participants without evidence of cognitive slowing at study entry did not show greater improvement on MPH than on placebo. Contrary to expectation, symptoms of depression did not respond better to MPH than to placebo, regardless of initial symptomatology. Information processing slowing in HIV-1 infection therefore appears amenable to pharmacologic intervention with the dopamine agonist MPH. However, results suggest clinicians should consider reserving the use of MPH for patients with more pronounced cognitive and affective deficits.