Circulating lymphocytes home to the mucosal lymphoid organs, Peyer’s patches (PP), through high endothelial venules (HEV). In situ analyses revealed that transfused lymph node cells (LNCs) interact with PP-HEV In a series of overlapping adhesion events: L-selectin (CD62L)> a467 Initiates interaction, L-selectin and a467 both participate in rolling, and Gai-linked activation triggers arrest that requires both a467 and LFA-1. a467 dramatically reduces rolling velocity, and appears to be required for engagement of LFA-1. In contrast with resting LNC, preactlvated LNC or~ 467~ lymphoma cells require only a467for arrest in PP-HEV. The predominant PP-HEV ligand for a467 but also apparently for L-se&tin is the mucosal addressin MAd-CAM-l. These results validate the concept of multlmolecular adhesion/decision cascades in physiologic lymphocyte-endothelial recognition, define a novel role for a4 in&grins as a ‘bridge” between selectln and 62 integrin-dependent events, and reemphasize the potential for direct adhesion through preactlvated a4 integrins alone.