The endogenous plasma anticoagulant proteins tissue factor pathway inhibitor (TFPI) and antithrombin (AT) have both been extensively studied in large, multinational phase III clinical trials in patients with severe sepsis. The TFPI and AT trials failed to result in significant reductions in the 28-day, all-cause mortality rates in their respective study populations. However, there appear to be definable patient populations within each study that may have benefited from TFPI or AT. Drug-drug interactions and dosing issues were observed in both trials. The similarities and differences of each anticoagulant and the lessons learned from the recent phase III clinical trials are examined in this review.