The conjugation of two lipophilic p-oxymethylbenzyl-3 beta-cholestanylsuccinate groups to fully benzylpenicilloylated eicosa-L-lysine [BPO20Lys20(OSuco)2] greatly potentiated its ability to suppress anti-BPO IgE antibody formation in vivo in mice. This enhanced tolerogenicity was due to the ability of BPO20Lys20(OSuco)2 to induce T suppressor cells (Luescher, I.F. et al., Eur. J. Immunol. 1984. 14: 68). In the present study the role of adherent cells in the induction of T suppressor cells by BPO20Lys20(OSuco)2 was investigated. Low numbers of macrophages pulsed in vitro with BPO20Lys20(OSuco)2, but not with the hydrophilic analog BPO21Lys20-OH, suppressed anti-BPO IgE antibody formation upon transfer into syngeneic recipients. This suppression was antigen and IgE specific, and was manifested in naive as well as in previously immunized mice. By cell transfer experiments it was found that the suppression was sensitive to cyclophosphamide. The IgE suppression was not due to carry-over of BPO20Lys20(OSuco)2 by the transferred macrophages since the amount of cell-associated antigen was approximately 500-fold too low to account for the observed suppressions. The capability of BPO20Lys20(OSuco)2 to elicit anaphylaxis in passively sensitized rats was significantly lower in comparison to the hydrophilic analog BPO21Lys20-OH. Adherent cells pulsed with BPO20Lys20(OSuco)2, although strongly suppressing IgE antibody formation, failed to elicit any detectable anaphylaxis. The role of adherent cells in the induction of T cell-mediated suppression of IgE antibody formation by lipid-modified antigens is discussed and novel therapeutical concepts to achieve desensitization of drug allergic individuals are suggested.