SummaryTolerance to soluble antigens has previously been shown to occur in mice if anti‐L3T4 monoclonal antibody (MoAb) is administered al 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 signaling 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 ∼1:102compared with ∼1:105in 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.