Glycolipid-enriched membrane microdomains ("rafts") are critical sites for signal transduction and other processes such as intracellular transport. While the participation of T-cell rafts in the formation of the immunological synapse is well established, the role of rafts on antigen-presenting cells (APCs) as well as the relationship between these domains and major histocompatibility complex (MHC) molecules is less clearly defined. We therefore investigated whether MHC class I or II molecules are found in rafts of the human macrophage-monocytic cell line U937. We detected the preferential localization of MHC class II, but not class I, molecules in rafts. Furthermore, raft disruption resulted in a decrease in constitutive protein tyrosine phosphorylation events in U937 cells. Our findings are reviewed in the context of results from other groups who also found important associations of MHC class II molecules with APC rafts. Additional, and at times contradictory, findings by others regarding the relationship between rafts and MHC molecules are also discussed. It is concluded that class II MHC molecules can localize in rafts of APCs and that this localization may be relevant for APC function and thus immune regulation.