The B cell surface receptor CD22 binds several sialoglycoproteins containing sialic acid in alpha 2,6 linkage, on the surface of B and T lymphocytes. Because lymphocytes adhere tightly to fibroblasts transfected with CD22 cDNA, it would appear reasonable to suggest that regulatory mechanisms might have evolved which prevent undesired CD22-mediated leukocyte aggregation. Here we provide evidence for the existence of at least one mechanism that might regulate CD22 interaction with ligands on adjacent cells. We demonstrate that sialylation of CD22 by beta-galactoside alpha 2,6-sialyltransferase abrogates CD22-mediated lymphocyte adhesion, and that adhesion can be restored by removal of alpha 2,6-linked sialic acid residues from the CD22 molecule. Taken together, our results suggest that alpha 2,6-sialyltransferase can both promote and inhibit CD22-ligand interactions. These observations provide the first direct evidence that receptor-ligand interactions mediated by an Ig superfamily molecule are under the control of a specific glycosyltransferase.