This study examined whether there are neuropsychological performance differences between human immunodeficiency virus–seropositive participants being followed at a University of Zambia clinic and demographically comparable seronegative controls being tested for infection in the same setting. All participants were administered a standardized neurocognitive test battery that has been found sensitive to HIV-associated Neurocognitive Disorder in the United States and internationally (e.g., in China, India, Romania, and Cameroon). The test battery was found to be applicable to a Zambian population. A clear HIV effect was seen with a medium to large overall effect size (Cohen d = 0.74). However, it was only the female seropositive participants who showed this HIV effect. HIV can result in neuropsychological deficits in Zambia, where clade C of the virus dominates. It is suggested that the HIV-infected women are more at risk of developing cognitive deficits than are men in this population, possibly because of sex-related social, financial, and healthcare disadvantages. However, further analyses are required regarding this conclusion because the finding was a result of an unplanned subanalysis.