In the dextran B512 high-responder strain C57BL, the response to dextran is restricted to the preferential expression of the V(H)B512 and the V(kappa)OX1 gene combination. The importance of the heavy chain is suggested by the fact that mice with the Ig C(H) allotype, different from C57BL, are low or non-responders to dextran, but the light chain could also play a role. All anti-dextran B512 mAb described to date (>200) use kappa light chains. No anti-dextran antibody using lambda has ever been observed. To ascertain if the restriction of the use of V(kappa) genes in response to dextran B512 was more stochastic or due to other factors, we have studied the response to dextran B512 in C57BL/6 mice where the C(kappa) domain has been disrupted (C57BL.C(kappa)T). These mice are unable to express kappa light chains and their humoral antibodies bear light chains of the lambda type. We found that C(kappa) knockout mice are unable to respond to dextran given in a thymus-independent or -dependent form. The lack of responsiveness is specifically directed to the dextran epitopes since these mice are fully competent to respond to other antigenic structures present in the same immunogenic molecule. These mice are also apparently normal regarding the expression of V(H) genes. Finally, we tested the response to dextran in C57BL.C(kappa)T mice carrying the lpr mutation that was introduced to favor an increase in the life span and make the response to dextran more easily detectable. The introduction of the lpr mutation was not sufficient to change the pattern of unresponsiveness in the C57BL.C(kappa)T mice. We concluded that there are deficiencies in the light chain repertoire because the V lambda light chain could not reconstitute the response to dextran. We discuss the possible mechanisms for this new type of unresponsiveness to dextran B512.