Mycobacterial fractions, some of which are associated with the cell envelope of Mycobacterium avium serovar 4, were assessed for their ability to affect various immunological functions of human peripheral blood mononuclear cells (PBM). Treatment of PBM with a total lipid fraction derived from M. avium serovar 4 resulted in a significant suppression of lymphoproliferative responsiveness to phytohemagglutinin stimulation at concentrations not affecting cell viability. Although a similar suppression was not observed when PBM were treated with purified serovar 4-specific glycopeptidolipids (GPL), treatment with the beta-lipid fragment derived from the GPL did result in a significant suppression of phytohemagglutinin responsiveness. Further studies revealed that the total lipid fraction and the beta-lipid fragment were effective at significantly reducing the ability of human macrophages to restrict the intracellular growth of mycobacteria and at stimulating PBM to secrete prostaglandin E2. These same effects were not observed when purified GPL or the reduced oligosaccharide fragment of the GPL was used. Other studies revealed that the total lipid and purified GPL fractions were effective at stimulating tumor necrosis factor alpha release from human PBM, whereas the beta-lipid fragment was not. These results indicate that mycobacterial lipids have various immunomodulatory capabilities, depending upon their chemical nature and ability to interact with certain host cells.