Quinolinic acid (QUIN) has been associated with several inflammatory neurologic disorders, including AIDS dementia complex (ADC). Recent studies suggest that activation of macrophages with either HIV-1 or interferon-γ (IFN-γ) can lead to QUIN production. However, the importance of other cytokines, especially those related to the macrophage and that are especially important in ADC pathogenesis, remains unclear. We, therefore, sought to determine the role of tumor necrosis factor-α (TNF-α) and IFN-α in the production of QUIN. Primary human macrophages were stimulated with two different concentrations of these cytokines alone, in combination with each other, and with IFN-γ. QUIN concentrations in the supernatants were then measured by mass spectrometry at 24, 48, and 72 hs. Results at 72 h showed significant increases in QUIN production in the cells stimulated with IFN-γ (10297 ± 170 nmol/L) and also in those stimulated with IFN-α (3600 ± 113 nmol/L), whereas TNF-α-stimulated macrophages produced low levels of QUIN (1108 ± 23 nmol/L). Macrophages stimulated with the cytokine combinations TNF-α and IFN-γ, IFN-α, and IFN-γ, and TNF-α and IFN-α also resulted in increases in QUIN production (11471 ± 77.6 nmol/L, 16656 ± 184 nmol/L, and 3369 ± 120.5 nmol/L, respectively). The increases in QUIN production in all of the cytokine treatments approached or exceeded in vivo concentrations of QUIN that have been shown to be neurotoxic. These data further support a role for QUIN in cytokine-mediated neuronal death in inflammatory disorders of the brain, especially ADC.