We have examined the capacity of monoclonal antibodies (mAb) specific for HLA class I heavy chain to interfere with the human immunodeficiency virus (HIV) replicative cycle in human T cells. Among six anti-HLA class I heavy chain-specific mAb assayed, two mAb, RL4-24-6 and W6/32, were able to delay HIV1 and HIV2 cytopathic effect on MT4 cells, a human T cell leukemia virus type I (HTLVI) immortalized T cell line, mAb RL4-24-6, chosen for further studies, also inhibited HIV1 production by peripheral blood mononuclear cells (PBMC), and this inhibition was dose dependent. However, no effect was observed when mAb treatment was performed with either the CEM or Jurkat T cell lines. Our investigation of how RL4-24-6 interferes with the HIV replicative cycle revealed that: (a) incubation of PBMC with RL4-24-6 prior to HIV exposure did not change the susceptibility of these cells to HIV infection, (b) syncytia formation between CD4+ MT4 cells and HIV chronically infected PBMC was not affected by RL4-24-6 and (c) treatment of freshly infected PBMC with RL4-24-6, however, inhibited viral production. These data, together with those we previously reported using anti-beta 2-microglobulin (beta 2m) mAb, suggest that anti-HLA class I/beta 2m complex mAb can modify an early step of the HIV replicative cycle without affecting the viral entry.