To evaluate the effects of goal-directed therapy on outcomes in high-risk patients undergoing cardiac surgery. A prospective randomized controlled trial and an updated metaanalysis of randomized trials published from inception up to May 1, 2015. Surgical ICU within a tertiary referral university-affiliated teaching hospital. One hundred twenty-six high-risk patients undergoing coronary artery bypass surgery or valve repair. Patients were randomized to a cardiac output-guided hemodynamic therapy algorithm (goal-directed therapy group, n = 62) or to usual care (n = 64). In the goal-directed therapy arm, a cardiac index of greater than 3 L/min/m was targeted with IV fluids, inotropes, and RBC transfusion starting from cardiopulmonary bypass and ending 8 hours after arrival to the ICU. The primary outcome was a composite endpoint of 30-day mortality and major postoperative complications. Patients from the goal-directed therapy group received a greater median (interquartile range) volume of IV fluids than the usual care group (1,000 625-1,500 vs 500 500-1,000 mL; p < 0.001, with no differences in the administration of either inotropes or RBC transfusions. The primary outcome was reduced in the goal-directed therapy group (27.4% vs 45.3%; p = 0.037). The goal-directed therapy group had a lower occurrence rate of infection (12.9% vs 29.7%; p = 0.002) and low cardiac output syndrome (6.5% vs 26.6%; p = 0.002). We also observed lower ICU cumulative dosage of dobutamine (12 vs 19 mg/kg; p = 0.003) and a shorter ICU (3 3-4 vs 5 4-7 d; p < 0.001) and hospital length of stay (9 8-16 vs 12 9-22 d; p = 0.049) in the goal-directed therapy compared with the usual care group. There were no differences in 30-day mortality rates (4.8% vs 9.4%, respectively; p = 0.492). The metaanalysis identified six trials and showed that, when compared with standard treatment, goal-directed therapy reduced the overall rate of complications (goal-directed therapy, 47/410 11% vs usual care, 92/415 22%; odds ratio, 0.40 95% CI, 0.26-0.63; p < 0.0001) and decreased the hospital length of stay (mean difference, -5.44 d; 95% CI, -9.28 to -1.60; p = 0.006) with no difference in postoperative mortality: 9 of 410 (2.2%) versus 15 of 415 (3.6%), odds ratio, 0.61 (95% CI, 0.26-1.47), and p = 0.27. Goal-directed therapy using fluids, inotropes, and blood transfusion reduced 30-day major complications in high-risk patients undergoing cardiac surgery.