People living with HIV/AIDS (PLWHA) in the United States (US) have disproportionately high rates of food insecurity (FI). In the general population, FI has been associated with cognitive impairment among older adults and may exacerbate HIV-associated neurocognitive disorders. The current study assessed the effects of FI and HIV infection on the neuropsychological performance of 61 HIV-positive and 36 HIV-negative adults in the US. While the main effects were minimal, the interactive effects revealed that FI was related to deficits in speed of information processing, learning, memory, motor function, and overall cognitive impairment for the HIV-positive group, but not the HIV-negative group. The interactive effects remained after controlling for relevant sociodemographic characteristics. Although bidirectional associations cannot be ruled out in a cross-sectional study, the results suggest that FI may contribute to cognitive impairment among HIV-positive adults in the US. Given the high rates of socioeconomic disadvantage among PLWHA in the US, addressing FI as part of routine clinical care may be warranted.