Antigen-specific major histocompatibility complex (MHC)-restricted helper T cell precursors were induced to proliferate in cultures of keyhole limpet hemocyanin-primed lymph node cells. Clones of F1 hybrid helper T cells were isolated in limiting-dilution cultures. Each positive culture at a limiting-dilution of lymph node cells gave rise to > 10 helper T cells with a single MHC-restricted specificity. This made it possible to independently assay specific helper activity of isolated clones in secondary cultures with B cells of diverse origin. Different clones with helper activity restricted to either parental or unique F1 hybrid MHC determinants were found to occur at approximately equal frequency. The results are discussed in relation to hybrid Ia specificities and dual-complementing MHC-linked Ir genes.