Significance Mismatch repair is the process that corrects replication errors. Mutations in the proteins MutSα and MutLα that initiate MMR are responsible for Lynch syndrome, the most common hereditary cancer. We present results showing surprising stoichiometries and conformations of human MutSα and MutLα mismatch repair initiation complexes. Moreover, these multimeric MutSα–MutLα complexes reconfigure the DNA in the vicinity of the mismatch. These complexes may not only mark the position of the mismatch but also could protect it from nucleosome reloading and potentially remodel adjacent nucleosomes. These results contrast with current models in the field, which envision mobile 1:1 MutSα–MutLα complexes that leave the mismatch. Our results provide a framework for thinking about MMR initiation.