Cellular cytotoxicity may be an important defense in the control of HIV progression. In the present study antibodies were attached to peripheral blood mononuclear cells (PBMC) by exposing them to polyethylene glycol and phthalate oil in the presence of HIV human hyperimmune IVIG (HIVIG). The attachment procedure is known as 'franking' and the resultant cytotoxicity is termed 'antibody-directed.' The majority of the cells that are franked with attached HIVIG are CD16+ (Fcγ RIII), placing them in the natural killer cell population. Franking increased the cytotoxicity of PBMC from both healthy controls and HIV-seropositive patients approximately fourfold compared to conventional antibody-dependent cellular cytotoxicity using CEM cells coated with HIV gp120 antigen as targets. Use of anti-HIV monoclonal antibodies for franking was less efficient than polyclonal HIVIG. The HIVIG-franked PBMC suppressed p24 production of in vitro HIV(IIIb)-infected human PBMC. The ability of HIVIG to enhance and direct cytotoxicity to HIV targets may suggest a new therapeutic approach to HIV control.