Horsley took him under his wing and showed him the basics. Subsequently, Crile began doing his own research and soon superseded his mentor with his award winning monograph, An Experimental Research Into Surgical Shock. .
When his apprenticeship in England was completed, Crile returned to the United States and immediately went to work as clinical professor of surgery in the Western Reserve School of Medicine. During this period of time Crile would make many groundbreaking discoveries that would shake the foundation of the medical profession. .
George Crile first aimed his efforts at making all surgeries as atraumatic as possible. He realized that the prevention of shock was of far greater importance than its treatment. To this end, he focused on creating bloodless methods of surgery. The first of his ingenious discoveries was the "pressure suit." The pressure suit was designed to restore blood to the circulation by the application of external pressure. The suit was very successful and would be used in years to come to prevent blackout of pilots subjected to high gravity forces. In addition to his pressure suits, Crile would use saline solutions and epinephrine to constrict the blood vessels of his patients, therefore preventing serious blood loss. .
However good these methods were, Crile knew that they were not miracle cures. He knew that patients could still die in spite of them. It was this unsettling truth that led him to the greatest discovery of his lifetime; the blood transfusion. George Crile conducted the first direct blood transfusion in 1905, between two people with type AB blood. He painstakingly connected the donor's artery to the recipient's vein for transfusion (later he devised a cannula to be used for this purpose). The staff was in awe as the once pale and sickly patient became rapidly and visibly healthier. When the patient recovered from potentially fatal surgery in record time Crile's new development became national news.