This investigation examined the effects of HIV-1 infection on speeded complex cognitive processing in a group of HIV-negative (n = 666), HIV-positive symptomatic (n = 156), and HIV-positive asymptomatic (n = 623) participants while controlling for the effects of slowed motor functioning, peripheral neuropathy, and several other putative confounds. Stroop Interference and reaction-time tasks served as anchor procedures to assess cognitive processing. The present findings suggest that HIV-1 infection is capable of compromising CNS-mediated cognitive processes (speeded processing) infringing upon their efficacy in the symptomatic stages of the disease while sparing individuals in the asymptomatic stage. The detrimental effects observed on information-processing mechanisms associated with HIV infection persisted despite the use of procedures to control for peripheral nerve integrity and other potential confounds.