Adult mice injected intravenously with fluorescein isothiocyanate (FL) conjugated to an isologous carrier (mouse IgG2a) (FL-MGG) or to a heterologous carrier (sheep γ-globulins) (FL-SGG) are rendered specifically unresponsive to the FL-hapten. Tolerance induced by either tolerogen persists upon adoptive transfer. Since cells with tolerogen on their surface are detectable by immunofluorescence in both experimental situations, we compared the persistance of such cells in the spleens of mice injected with either tolerogen or with an immunogen (FL-KLH). FL-binding cells were seen during the first 5 days after the injection of FL-SGG, but were undetectable by day 7 and thereafter. In contrast, fluorescent cells were detectable up to 20 to 30 days in some animals after FL-MGG, although the number decreased after day 11. FL-binding cells decreased significantly after day 1 in FL-KLH-injected mice. When the number of FL-binding cells in tolerant animals had reached baseline levels, the animals were reinjected with their respective tolerogen. Normal or slightly increased numbers of FL-binding cells were found in the spleens of FL-SGG injected mice, whereas decreased numbers were observed in the spleens of FL-MGG injected mice. This suggests that in tolerance induced by heterologous carrier, specific lymphocytes possess free receptors but cannot respond. On the other hand, with the isologous carrier-induced tolerance, free receptors are either not available (modulated?) or blocked with undectable amounts of tolerogen. Whether this difference in the kinetics represents a difference in the mechanism of tolerance is unknown.