Binding of secretory IgA (sIgA) to human milk macrophages was identified by rosette formation with sIgA-sensitized indicator cells and competitive inhibition binding studies with [125I]-sIgA. Macrophages formed rosettes with sIgA-sensitized sheep red blood cells that were inhibited by sIgA (87%) but not IgG. Both IgA1and IgA2inhibited sIgA-sensitized sheep red blood cell rosette formation. Rosette formation was completely inhibited by galactose, partially inhibited by asialofetuin, and unaffected by mannose. [125I]-labeled sIgA binding to macrophages reached a plateau after 60 min, was dependent on the number of macrophages in culture, and was specifically inhibited by unlabeled sIgA. Incubation of macrophage monolayers with increasing concentrations of sIgA-anti-IgA immune complexes resulted in a progressive increase in the oxidative burst and increased secretion of prostaglandins. These studies indicate that human milk macrophages have a receptor for sIgA and that activation of these macrophages may occur via these receptors.