Cell adhesion mediated by the integrin a4b1 plays a key role in many biological processes reflecting both the number and functional significance of a4b1 ligands. The lipopolysaccharide (LPS) receptor, CD14, is a GPI-linked cell surface glycoprotein with a wide range of reported functions and associations, some of which overlap with that of a4b1. This overlap led us to test the specific hypothesis that a4b1 and CD14 interact directly. Jurkat T cells (a4b1 + ) were found to adhere to a recombinant CD14-Fc protein via a4b1, whilst K562 cells (a4b1 À ) did not. However, stable reexpression of the a4-subunit conferred this ability. The adhesion of both cell types to CD14 displayed activation state-dependent binding very similar to the interaction of a4b1 with its prototypic ligand, VCAM-1. In solid-phase assays, CD14-Fc bound to affinity-purified a4b1 in a dose-dependent manner that was induced by activating anti-b1 mAbs. Finally, in related experiments, JY cells (a4b7 + ) were also found to attach to CD14-Fc in an a4-dependent manner. In summary, CD14 is a novel ligand for a4b1, exhibiting similar activation-state dependent binding characteristics as other a4b1 ligands. The biological relevance of this interaction will be the subject of further studies.