The characteristic cell type involved in Langerhans cell histiocytosis, 'LCH cells', express most of the enzyme histochemical and immunocytochemical markers of normal epidermal Langerhans cells. It is not known, however, whether these LCH cells express the functional characteristics of normal epidermal Langerhans cells. We studied the alloantigen-presenting activity of LCH cells derived from lesional sites of three patients with the disease. Lesional cells expressing the CDla molecule were enriched using either fluorescein-activated cell sorting or negative selection with indirect immunomagnetic beads, and functional activity was assessed using the 6-day primary allogeneic mixedlcell reaction. Compared to epidermal Langerhans cells from healthy controls, LCH cells showed minimal alloantigen-presenting activity on a per-cell basis. The diminished activity was not reversed by exogenous prostaglandin synthetase inhibitor or recombinant human IL-I[3. This study confirms our previous report of a child, with fatal multisystem Langerhans cell histiocytosis suggesting that this disease represents a condition in which functionally defective cells of Langerhans cell phenotype accumulate and/or proliferate in various tissues. We postulate that the functional defect is a primary defect of these LCH cells that have acquired an as-yet-undetermined biological insult(s).