Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS) and disseminated intravascular coagulation (DIC) may have identical manifestations in adults. Because TTP-HUS is 90% fatal without plasma exchange, prompt diagnosis is essential. To test the hypothesis that routine laboratory assays can discriminate between the 2 entities, we retrospectively identified adult patients with TTP-HUS and matched each with 2 patients with DIC. Although the platelet count, prothrombin time (PT), and partial thromboplastin time were different (P < .05) between the 2 patient groups, after regression analysis, only PT and profound thrombocytopenia remained associated with TTP-HUS (P = .001 and P = .003, respectively). A platelet count of less than 20 × 103/μL (20 × 109/L) and a PT within 5 seconds of the upper limit of the reference interval had a specificity of 92% for TTP-HUS. Our data confirm that readily available laboratory assays in the proper clinical scenario can increase the likelihood of TTP-HUS over DIC.