Only limited data on cerebrospinal fluid (CSF) HIV-1 RNA responses and markers of local inflammation in CSF during antiretroviral therapy are available. HIV-RNA, soluble tumor necrosis factor (TNF)-receptor (sTNFr)-II, monocyte chemoattractant protein (MCP)-1, and interferon-gamma-inducible protein (IP)-10 were measured in the peripheral blood and CSF of 26 antiretroviral-naive HIV-1-positive patients, who were treated with ritonavir (RTV)/saquinavir (SQV) (n = 5), RTV/SQV/stavudine (d4T; n = 8) or zidovudine (AZT)/lamivudine (3TC)/abacavir/nevirapine/indinavir (n = 13). After 8 to 12 weeks of treatment, CSF HIV-RNA dropped to <400 copies/ml in 1 of 5 patients in the RTV/SQV group, 8 of 8 patients in the RTV/SQV/d4T group, and 9 of 10 patients in the five-drug group. CSF sTNFr-II and IP-10 levels increased in patients with detectable CSF HIV-RNA. However, increases in CSF chemokine and sTNFr-II concentrations were also observed in some patients with good CSF HIV-RNA responses. Moreover, CSF MCP-1 concentrations increased in the whole population after 2 months of treatment. Ongoing residual HIV replication in the central nervous system, which cannot be detected with CSF HIV-RNA measurements, may account for this phenomenon.