Antibody-dependent cellular cytotoxicity (ADCC) against murine enteropathogenic bacteria such as Salmonella typhimurium and Salmonella tel aviv or Shigella X16 was assessed by using IgG, IgA, and secretory IgA (sIgA) in a 2-hr in vitro assay where peripheral and intestinal lymphocytes were used as effector cells. It was found that IgG could arm splenocytes (SpL) better than IgA. However, IgG did not arm lymphocytes from Peyer's patches (PPL) or from mesenteric lymph nodes (MnL), whereas IgA of plasmacytoma origin against S. tel aviv and purified intestinal sIgA against Shigella X16 induced specific antibacterial ADCC with both SpL and PPL. When sIgA were tested with intestinal lymphocytes from the epithelium and the lamina propria, i.e., cells from the gut mucosa which first interact with enteric bacteria, it was found that both these lymphoid populations were able to express sIgA-dependent ADCC against Shigella X16. In parallel tests, cells from thymus and popliteal lymph nodes failed to express ADCC. Blocking studies with purified IgG and IgA of goat, rabbit, and mouse origin demonstrated that the Fc-alpha and Fc-gamma receptors were specifically involved in IgA- or IgG-dependent antibacterial ADCC. At least two effector populations, a macrophage and a Thy-1.2- lymphocyte, were observed to exert IgA-ADCC at the splenic level, whereas only lymphoid cells expressed this activity at the GALT level. Together, these results describe a new activity of IgA against enteropathogenic bacteria.