The neural cell adhesion molecule L1 has been implicated in a variety of neurologic processes, including neuritogenesis and cerebellar cell migration. Here we propose an expanded role for this cell adhesion molecule in the human immune system based on its expression on cells of myelomonocytic and lymphoid origin. Freshly isolated circulating monocytes had minimal L1 expression; however, activation of these effector cells by IFN-gamma, or as a result of density gradient isolation, resulted in a significant induction of L1 expression. Constitutive L1 expression was further evident on myelomonocytic cell lines but was absent on mature tissue macrophages. In further studies, positive selection with a L1-specific Ab enriched both B cells and dendritic precursor cells from peripheral blood. Significantly, L1 expression was not detected on mature dendritic cells but could be induced by treatment with LPS, PHA, and TNF-alpha. Immunohistochemical analysis further demonstrated significant L1 expression on follicular dendritic cells and on endothelial cells associated with the arterioles and red pulp of normal spleen. Based on these observations and known functions of L1, we propose that this cell adhesion molecule may contribute to cell-cell adhesion events associated with the effector function or extravasation of these immune effector cells. In support of the latter, we present evidence that L1 can be recognized by endothelial cells via the integrin alpha(v)beta3.