GEORGE W. CRILE is best known as the father of physiological surgery in the United States, a pioneer surgeon, an innovator and inventor, a founding member of the American College of Surgeons, and the principal founder of the Cleveland Clinic Foundation. However, Crile's legacy of performing the first direct blood transfusion in humans has been all but forgotten, even though the results were published in the leading scientific journals of the day. Crile's lifelong interest in the treatment of surgical shock led to his interest in blood transfusion. A chance visit to the laboratory of Alexis Carrel in 1902 resulted in Crile perfecting his technique for direct blood transfusion. He subsequently modified Carrel's anastomosis technique to administer a faster transfusion, investigated the use of blood transfusions in various clinical settings, and went on to introduce the concept and technique of blood transfusion to soldiers during World War I. In this report, we trace his long-time interest in blood transfusion and document the events that led to the first successful blood transfusion performed between 2 brothers on August 6, 1906, at St. Alexis Hospital, Cleveland, OH.