A case-control study was performed to determine the impact of aprotinin or tranexamic acid use on reducing intraoperative blood loss and transfusion needs in complex spine surgery. Sixty-nine patients undergoing complex spine surgery received aprotinin or tranexamic acid. The aprotinin group contained 30 patients (8 men and 22 women) and the tranexamic acid group 39 patients (11 men and 28 women). The following variables were recorded: duration of surgery, number of levels fused, intraoperative and total blood loss, and number of blood units transfused (autologous and allogenic). In addition, various parameters related to blood loss in this type of surgery were calculated. The groups differed with regard to duration of surgery (aprotinin 662 min vs tranexamic acid 448 min, P<.001) and number of levels fused (aprotinin 11.2 vs tranexamic acid 7.6, P=.004). There were no significant differences in intraoperative blood loss (aprotinin 2118 mL vs tranexamic acid 1608 mL, P=.066) or total blood loss (aprotinin 3312 mL vs tranexamic acid 2627 mL, P=.056). Statistical differences were found for the number of autologous blood units transfused (aprotinin 2.2 vs tranexamic acid 1.3 P=.047) and total units transfused (aprotinin 4.1 vs tranexamic acid 2.6, P=.008). Blood loss per hour of surgery, transfused units per level fused, and transfused units per hour of surgery were similar in the 2 groups. Significant differences were found for intraoperative blood loss per fusion level (aprotinin 228 mL vs tranexamic acid 428, P=.025) and total blood loss per fusion level (aprotinin 360 mL vs tranexamic acid 638 mL, P=.01). Analysis of the applied geometric mean showed that aprotinin reduced total blood loss by 16.4% and total number of blood units transfused by 12.4% as compared to tranexamic acid, although statistical significance was not reached. The type of antifibrinolytic used did not have a significant impact on the main outcome variables of the study.