Thrombotic thrombocytopenic purpura is a catastrophic disease and may occur in the presence of other confounding diseases. We present a case of TTP in a patient with connective tissue disease and HIV infection, in whom the diagnosis and management of TTP was challenging. It is important to understand the various underlying mechanisms that drive TTP in the presence of these comorbid diseases, so that an appropriate treatment strategy can be initiated. Our patient failed an initial trial of plasma infusion alone, but responded well to plasma exchange.