In the course of maturation in the thymus there is a selection of T lymphocytes based on the avidity between their T-cell receptors and HLA/peptide complexes expressed on stromal thymic cells. The repertoire of mature T lymphocytes is further modulated by encounters with foreign antigens. Thus, the antigen specific repertoire of the peripheral T-lymphocyte pool is determined by genetic and environmental factors. We recently reported that pairs of monozygotic twins often display significant differences in their allospecific cytotoxic T-cell repertoire, suggesting an important role of confrontation with foreign antigens on the CD8+ T-cell repertoire. We have now performed similar studies on the repertoire of allospecific CD4+ T lymphocytes. Using positively selected CD4+ T cells in limiting dilution analyses we compared the differences in the allospecific helper T-lymphocyte precursor frequencies(HTLpf) between pairs of genetically identical monozygotic twins and pairs of unrelated, HLA disparate individuals. We found that all monozygotic twin pairs and most unrelated pairs had similar HTLpf to the same stimulator, i.e., the 95% confidence intervals were overlapping. However, when studied in greater detail, the differences in HTLpf within monozygotic twin pairs were found to be significantly smaller than the differences within pairs of unrelated responders. Thus, we find evidence of an influence by environmental antigens also on the repertoire of allospecific CD4+ T cells, but polymorphic genetic factors seem to be more important here than for the repertoire of allospecific CD8+ T cells.