Spine surgery has been growing rapidly as a neurosurgical operation, with an increase of 220% over a 15-year period. Intraoperative blood transfusion is a major outcome determinant of spine procedures. Various approaches, including pharmacologic and nonpharmacologic therapies, have been tested to decrease both intraoperative and postoperative blood loss. The aim of this systematic review is to report clinical evidence on the relationship between intraoperative blood loss (primary outcome) and on transfusion requirements and postoperative complications (secondary outcomes) in patients undergoing spine surgery. A literature search of PubMed database was performed using 5 key words: spine surgery and transfusion; spine surgery and blood loss; spine surgery and blood complications; spine surgery and deep vein thrombosis; and spine surgery and pulmonary embolism. Clinical reports (randomized controlled trials, prospective and retrospective studies, and case reports) were selected. A total of 473 articles were examined; 450 were excluded, and 24 were selected for this systematic review. Selected articles were categorized into 3 subchapters: (1) drugs active on coagulation (12 studies): tranexamic acid, aminocaproic acid, aprotinin, and recombinant activated factor VII; (2) drugs not active on coagulation (5 studies): ketorolac, epoetin alfa, magnesium sulfate, propofol/sevoflurane, and omega-3 and fish oil; (3) nonpharmacologic approaches (7 studies): surgical tips, patient positioning, and general or spinal anesthesia. Several studies have shown a significant reduction in intraoperative bleeding during spine surgery and in the requirement for blood transfusion.