We chronicle a case of an atypical plasmablastic proliferation in a patient occurring in the context of vedolizumab, a novel therapy for the treatment of inflammatory bowel disease (IBD). No documented cases exist of this potential association, and we propose a pathogenic mechanism. A 22-year-old female with IBD had a flare of colitis and required a subtotal colectomy. She had been on vedolizumab for 2 years. Histology revealed indeterminate colitis but discovered a densely cellular polypoid lesion of plasmablasts and plasma cells of varying maturation, positive for MUM1, BLIMP1, c-myc, IgG, and CD138, with a lambda light chain restriction, but negative for CD20 and PAX5. The combined diagnosis was of an atypical plasmablastic proliferation that mimicked a plasmablastic lymphoma; however, this diagnosis was confounded by its atypical presentation: a young female on vedolizumab, and we queried what pathogenic role vedolizumab may have had. Vedolizumab selectively targets α 4 β 7 integrin, a leucocyte adhesion molecule, to inhibit gut lymphocyte accretion and reduce inflammation. A similar phenomenon occurs with HIV-infection. HIV-gp120 binding with α 4 β 7 leads to a loss of gut CD4 + lymphocytes and the potential to develop plasmablastic lymphoma, an AIDS-defining diagnosis. Concurrent use of vedolizumab at diagnosis suggests a synergistic causal effect given the molecular mimicry of its target α 4 β 7 seen also with HIV-infection. This is the first documented case of a plasmablastic proliferation, or of any clonal cellular proliferation, to occur in the context of vedolizumab. α 4 β 7 integrin antagonism may carry oncogenic sequelae, and we recommend further investigation to understand its pathogenesis. KeywordsPlasmablastic proliferation • Plasmablastic lymphoma • Vedolizumab • α 4 β 7 integrin • α 4 integrin * Seosamh McCauley