I NTRAVENOUS (IV) heparin was frequently considered a treatment option in acute ischemic stroke. However, only limitation of thrombus growth and facilitation of spontaneous endogenous thrombolysis are reasons to believe in its value in treating the index stroke. Most clinicians nowadays agree that the use of heparin, either IV or subcutaneously (SC), prevents deep venous thrombosis and pulmonary embolism. However, the question remains whether heparin does prevent recurrent stroke. In view of the potential hemorrhagic complications and heparin-induced thrombocytopenia, early treatment with IV heparin has always been a matter of controversy. In 1994, the Stroke Council of the American Heart Association did not recommend heparin because data about safety and efficacy were insufficient and conflicting. Nevertheless, in the absence of other acute treatment options and with proved primary and secondary preventive effects of oral anticoagulation in cardioembolic stroke, IV heparin was frequently applied in several parts of the world. Although such treatment was used for decades, the first placebocontrolled, randomized trial addressing full-dose unfractioned heparin treatment in acute stroke was the one performed by the Cerebral Embolism Study Group. The study was terminated early because of excess mortality in the placebo arm. Later, statisticians and others claimed that the termination of the trial was premature and that there could be a type II error explaining the difference in early mortality. In another study, Duke and coworkers found no significant difference between IV heparin and placebo in a small number of patients with presumably noncardioembolic stroke. From 1995 on, important studies on anticoagulation early after stroke have been published. In the Hong Kong Study, therapy with SC nadroparin calcium was safe and beneficial at 6 months (primary outcome variable) but not at 3 months or 10 days after stroke. The larger follow-up Fraxiparine in Ischaemic Stroke Study, however, failed to replicate the positive aspects of the Hong Kong Study. In the Trial of ORG 10172 in Acute Stroke Treatment study, an intravenously administered heparinoid (danaparoid sodium) showed a positive response to treatment at 7 days, but not at 3 months (primary outcome variable). In this trial, the risk of recurrent stroke within 1 week was very low (1.2%) and was similar in different stroke subtypes. In post hoc analyses, patients with stroke from large-artery atherosclerosis (n = 230) had a benefit from treatment with danaparoid. In the Trial of ORG 10172 in Acute Stroke Treatment, the factor Xa–adjusted use of the heparinoid was associated with an increased risk of extracranial and intracranial hemorrhage, especially in patients with large stroke. Particularly since the International Stroke Trial, treatment with heparin has increasingly come under fire. The International Stroke Trial used a high dose of twice-daily SC heparin, which in some patients probably led to systemic anticoagulation. However, there was no systematic assessment of the activated partial thromboplastin time to monitor anticoagulant effects. Certainly, the results of twice-daily SC heparin cannot be used as proof against full-dose IV heparin with proper monitoring of activated partial thromboplastin time, mandatory computed tomographic scanning before therapy, and formal exclusion criteria for anticoagulant treatment, such as severe cerebral microangiopathy, large cerebral infarcts, and uncontrolled severe hypertension. Because of the factorial design of the International Stroke Trial, many patients receiving either dose of heparin also received aspirin, which makes the assignment of complications to one part of the treatment probably more difficult than assumed. In the absence of blinding, there may be a bias toward assigning bleeding complications to the presumably more dangerous drug. All data reviewed so far stem from randomized trials. The inclusion of patients into such trials is based on detailed inclusion and exclusion criteria. Once patients are entered, the prescribed treatment follows, mostly with strict dosaging and treatment times. Clinical practice is different: treatment may be halted, reinstituted, or, most importantly, prematurely terminated if the supposed cause of stroke for which anticoagulation was chosen is not confirmed. There are few data about the safety of anticoagulation in a routine clinical setting. In the European Cooperative Acute Stroke Study I, the European trial of tissue plasminogen activator, it was up to the local investigators to use heparin 24 hours after stroke IV, SC, or From the Neurology Department, University of Heidelberg, Heidelberg, Germany. CONTROVERSIES IN NEUROLOGY