Cancer-associated thrombotic microangiopathy (TMA) is a rare but serious condition seen in patients diagnosed with malignancy. Certain tumor characteristics highlight this entity, such as large tumor burden, adenocarcinoma histology with mucinous features and bone marrow infiltration. Although these tumors may originate from any site, the majority are of stomach, breast or prostate origin. The optimal therapy is unknown but there is evidence that immediate initiation of an effective antineoplastic regimen is important. However, it is difficult to differentiate cancer-associated TMA from primary thrombotic thrombocytopenic purpura in a timely manner. We present the first case of cancer-associated TMA in a patient secondary to a locally advanced gallbladder adenocarcinoma that lacked mucinous features and bone marrow involvement. The clinical presentation closely mimicked primary thrombocytopenic purpura and led to the ineffective use of plasma exchange. Nonetheless, the patient eventually received systemic chemotherapy and had a remarkable response by the resolution of her TMA.