Tolerance to soluble antigens has previously been shown to occur in mice if anti-L3T4 monoclonal antibody (MoAb) is administered at the time of antigen exposure. The process of tolerance induction may require the depletion of L3T4+ cells or it may be due to down-regulation or negative signalling of L3T4+ cells. We compared the effects of L3T4+ cell depletion and L3T4 antigen blockade at the time of primary antigen challenge on long-term humoral responses. Anti-L3T4 MoAb GK1.5 (IgG2b) and H129.19 (IgG2a) were used to deplete or block, respectively, L3T4+ cells. Following a short course of MoAb and antigen challenge with both aggregated human IgG (ag-HGG) and ovalbumin (OVA) in each mouse, primary response titres to each antigen in both MoAb treated groups were approximately 1:10(2) compared with approximately 1:10(5) in control mice. Repeated antigen challenge significantly increased the anti-OVA titre in both MoAb treated groups and by 150 days they were similar to controls. However, anti-HGG titres did not increase significantly in either of the MoAb treated groups. Thus either depletion of peripheral L3T4+ cells, or blockade of the L3T4 antigen without depletion of peripheral L3T4+ cells, can invoke a state of long-term antigen-specific tolerance to some antigens. Why the effect is restricted to particular antigens, and the exact mechanisms of tolerance induction remain to be determined.