Background: The role of prophylactic levosimendan in patients undergoing cardiac surgery is controversial. Methods: We performed a computerized search of Medline, Embase, and Cochrane databases through September 2017 for randomized trials evaluating the prophylactic use of levosimendan in patients undergoing cardiac surgery (ie, patients without low cardiac output syndrome). The main study outcome was mortality at 30 days. Results: The final analysis included 16 randomized trials with total of 2,273 patients. There was no statistically significant difference in mortality at 30 days between levosimendan and control groups (relative risk 0.68, 95% confidence interval [CI]: 0.45 to 1.03). Subgroup analysis showed no statistically significant difference in mortality at 30 days for patients with reduced left ventricular ejection fraction compared with patients having preserved left ventricular ejection fraction (p for interaction = 0.12). Further analysis suggested that levosimendan might be associated with improved mortality at 30 days when compared with active-control but not when compared with placebo (p for interaction = 0.01). The levosimendan group had a significant reduction in acute kidney injury (relative risk 0.59, 95% CI: 0.38 to 0.92), intensive care unit stay (standardized mean difference = −0.21, 95% CI: −0.29 to −0.13), and ventilation time (standardized mean difference = −0.43, 95% CI: −0.61 to −0.25), whereas it had higher rates of atrial fibrillation (relative risk 1.11, 95% CI: 1.00 to 1.24). No statistically significant differences were observed between groups in mortality beyond 30 days, postoperative dialysis, or myocardial infarction. Conclusions: Prophylactic use of levosimendan does not appear to reduce the mortality at 30 days or beyond 30 days in patients undergoing cardiac surgery. This lack of benefit was noted irrespective of the LVEF.