The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naive adults with median duration of infection of 75 days relative to a sample of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States, a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly fivefold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, the results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.