Objective: The effectiveness and safety of aprotinin use in cardiac surgery have been questioned. More data reflecting everyday clinical practice from large-scale, unselected populations are needed. We compared the effectiveness and safety of aprotinin in cardiac surgery with those of tranexamic acid in a follow-up study using the population-based Danish health-care databases. Methods: We identified a total of 3535 patients who underwent cardiac surgery at the Aarhus University Hospital, Skejby, between 1 January 2003 and 31 December 2006; of these, 635 patients were treated with aprotinin and 2900 with tranexamic acid. We used propensity score matching to match aprotinin-treated patients with tranexamic-acid-treated patients in a 1:1 ratio, followed by Poisson regression analysis to compute relative risks (RRs). Results: Patients treated with aprotinin had more severe preoperative risk profiles than the tranexamic-acid-treated patients. The rates of postoperative drainage and transfusion of red blood cells were similar in the two groups, whereas the aprotinin group received plasma (adjusted RR = 1.39; 95% confidence interval (CI): 1.15–1.68) and platelets (adjusted RR = 1.47; 95% CI: 1.19–1.81) more frequently than the tranexamic acid group. There were no statistically significant differences in risks of re-operation due to bleeding (adjusted RR = 1.22; 95% CI: 0.84–1.78), 30-day mortality (adjusted RR = 1.03; 95% CI: 0.69–1.54), acute myocardial infarction (adjusted RR = 1.06; 95% CI: 0.69–1.64), stroke (adjusted RR = 1.36; 95% CI: 0.75–2.44) or composite major event (adjusted RR = 1.14; 95% CI: 0.87–1.50) between the two groups. However, patients who received aprotinin had an increased risk of postoperative dialysis (adjusted RR = 1.76; 95% CI: 1.15–2.70). Conclusions: Aprotinin treatment was associated with an increased use of plasma and platelet transfusion and an increased risk for postoperative dialysis, but not with other adverse outcomes, including short-term mortality.