Essential help for long-lived alloantibody responses is theoretically provided only by CD4 T cells that recognise target alloantigen, processed and presented by the allospecific B cell. We demonstrate that in an alloresponse to multiple MHC disparities, cognate help for class-switched alloantibody may also be provided by CD4 T cells specific for a second ‘helper’ alloantigen. This response was much shorter-lived than when help was provided conventionally, by helper T cell recognition of target alloantigen. Nevertheless, long-lasting humoral alloimmunity developed when T cell memory against the helper alloantigen was first generated. Co-stimulatory blockade abrogated alloantibody produced through naive helper T cell recognition of target alloantigen, but crucially, blockade was ineffective when help was provided by memory responses to the accessory helper alloantigen. These results suggest that memory helper T cell responses against previously-encountered graft alloantigen may be the dominant mechanism for providing help to generate new specificities of alloantibody in transplant patients receiving immunosuppression.