Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare acute prothrombotic disorder caused by adenovirus vector-based COVID-19 vaccines or by viral infections. VITT results when high-avidity anti-PF4 antibodies of IgG class are generated that recognize antigens in the region of the heparin binding site on PF4. These antibodies cross-link PF4, which results in large multimolecular PF4/IgG immune complexes, activating platelets, monocytes, and neutrophils via their Fcγ receptors. Acute VITT that follows vaccination or virus infection is a secondary immune reaction. It is restricted to individuals with a specific genetic haplotype of the IgG light chain hypervariable region (IGLV21*02/03) and features an additional somatic mutation at position 31, resulting in a negatively charged paratope. This somatic hypermutation occurs in only one or a few B cell clones during boosting of the anti-PF4 immune response; therefore, VITT antibodies are mono- or oligoclonal. Patients with acute VITT develop thrombocytopenia beginning at least 4 days postvaccination/virus infection, and present with thrombosis, often at unusual sites (e.g., approximately 50% have cerebral venous sinus thrombosis [CVST] and 20% have splanchnic vein thrombosis); very high D-dimer levels are characteristic, and approximately one-third have hypofibrinogenemia. A subset of patients presents with severe headache prior to radiologically demonstrable CVST. Recently, a chronic prothrombotic disorder associated with VITT-like antibodies has been recognized, most often in association with a monoclonal gammopathy of thrombotic significance (VITT-like MGTS) in which the M-protein consists of anti-PF4 antibodies. These patients are not genetically restricted and present with recurrent, often unusual thromboses that can be refractory to conventional therapeutic-dose anticoagulation, in association with chronic or intermittent thrombocytopenia. The laboratory diagnosis of acute and chronic VITT is based on the demonstration of anti-PF4 antibodies, which strongly activate platelets in the presence of PF4. Acute treatment is based on therapeutic-dose anticoagulation and inhibition of Fcγ receptor-dependent activation of blood cells by high-dose intravenous immunoglobulins (IVIG), or removal of antibodies by therapeutic plasma exchange. Treatment of chronic VITT-like MGTS also includes eradication of the plasma cell clone. In treatment-resistant patients, Bruton kinase inhibitors (e.g., ibrutinib) dampen Fcγ receptor signaling, reducing platelet activation and hypercoagulability. This chapter addresses the clinical presentation and laboratory diagnosis of VITT and VITT-like anti-PF4 disorders and summarizes recent findings on its pathogenesis. Basic aspects of VITT treatment are briefly summarized.