Patients presenting with the syndrome of microangiopathic hemolysis and thrombocytopenia, without Shiga toxin-associated colitis, have thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Prognosis for TTP/HUS has changed over time from a fatal disorder associated with the classic pentad to a syndrome associated with 80% survival in the plasma exchange era. A growing number of mechanisms, including but not exclusive to severe ADAMTS13 deficiency, are now understood to result in this syndrome, and the prognosis of patients with TTP/HUS is related to many additional factors. This update on prognosis explores recent registry data studying both acquired idiopathic and also familial or recurrent forms of TTP/HUS, to delineate how mortality varies by underlying disease mechanism. This paper also explores the association between mortality and clinical presenting features, as well as whether the case is a primary or relapsed presentation. Recent data support an understanding of TTP/HUS as a heterogeneous syndrome with variable mortality, and with specific subgroups demonstrating an excellent outcome.