A severe autoantibody-mediated ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) deficiency caused immune-mediated thrombotic thrombocytopenic purpura (iTTP), a life-threatening illness. Acute iTTP episodes were a medical emergency, yet over >95% of patients survive if they were appropriately treated. However, at least half of the survivors would relapse at some point. Anti-ADAMTS13 Abs and a relapsing course were poorly understood, as were the mechanisms that contributed to the re-emergence of anti-ADAMTS13 Abs and a relapsing course. Anti-idiotypic Abs that counteract and neutralize harmful autoantibodies lead to remission in acquired hemophilia and systemic lupus erythematosus. To explore if anti-idiotypic Abs play a role in iTTP, researchers used phage display to select and amplify the splenic anti-idiotypic IgG1Fab κ/λ repertoire of 2 relapsing iTTP patients on previously prepared monoclonal inhibitory anti-ADAMTS13 Fabs. Although both patients shared four H chain V region genes (VH1-69*01, VH3-15*01, VH3-23*01, and VH3-49*03), investigators got 27 single anti-idiotypic Fab clones, half of which had distinct sequences. The inhibitory power of the monoclonal anti-ADAMTS13 Abs utilized for their selection was completely neutralized by the anti-idiotypic Fab pools of both individuals. Anti-idiotypic Fab pools neutralized functional ADAMTS13 inhibitors and restored ADAMTS13 activity in 18–45% of plasma samples from 22 unrelated iTTP patients stratified by functional ADAMTS13 inhibitor titers (>2 Bethesda units/ml, or 1–2 Bethesda units/ml). When taken jointly, they offered evidence for an anti-idiotypic immune response in iTTP patients. Despite reasonably homogeneous pathogenic anti-ADAMTS13 Abs identifying a prominent epitope in the ADAMTS13 spacer region, the interindividual generalizability of this reaction was restricted.