Increases in serum and cerebrospinal fluid (CSF) neopterin concentrations accompany many inflammatory diseases, including infection with HIV-1 and may reflect activation of guanosine triphosphate (GTP) cyclohydrolase I by γ-interferon and other cytokines. In the present study, macaques with clinical simian AIDS (SAIDS) infected with the immunosuppressive type-D retrovirus D/1/California had increased concentrations of CSF neopterin but not of biopterin beginning soon after seroconversion. Normal neopterin concentrations in the CSF were found in macaques with SAIDS-related complex as well as asymptomatic, viremic macaques. CSF biopterin, serum neopterin and serum biopterin concentrations of D/1/California-infected macaques were not different from the levels in control animals. The increase in CSF neopterin may reflect local inflammatory responses and paralleled previously documented changes in L-tryptophan metabolism in these macaques. However, the absence of macrophage infiltrates in the brain of the infected macaques suggests a non-macrophage source of both increased CSF neopterin and tryptophan metabolites in the SAIDS macaques.