AIDS pathogenesis results from a complex array of immune alterations which include, among others, changes in the pattern of cytokine production. Some monocyte-derived cytokines, like TNFalpha play a major role in HIV pathogenesis. TNFalpha transactivates HIV NF-kB thereby inducing viral replication, potentiates HIV replication in lymphomonocytes TNFalpha is one of the main factors of HIV-induced cachexia and might be involved in HAART-associated lipodystrophy. In addition, monocytes are infectable by HIV in vitro and infected monocytes can be recovered from the blood of HIV infected patients. For these reasons, we tested whether renewal of the pool of circulating monocytes by selective monocyte apheresis may improve the immune reconstitution which follows treatment with highly active anti-retrovirals (HAART). HIV-infected HAART receiving (> 1 year) patients who were either virologically non-responders (HIV-1 RNA >50,000 copies/ml) or immunologically non-responders (CD4 counts < 200) were treated with a novel monocyte apheresis device (G-1 Adacolumn). Plasma HIV viral load, proviral DNA and phenotypic and functional immunological analyses were performed. G-1 apheresis was well tolerated, not accompanied by adverse responses, and followed by clinical improvement. TNFalpha production was suppressed and CD4 T cell counts increased. In one G-1 patient with elevated HIV-1 proviral DNA a significant reduction (from 1,500 to 40 copies/10(5) cells) was observed. Neither immunologic nor virologic parameters were modified in the control patients who received HAART alone. Thus, purging of circulating monocytes by G-1 apheresis has a dramatic suppressive effect on TNFalpha production and is followed by both clinical and immunovirological improvement. G-1 apheresis should be considered in patients in whom HAART is only partially effective.