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The effect of a single-dose systemic acetaminophen to treat postoperative pain has been previously quantified, but the effect of systemic acetaminophen to prevent postoperative pain is currently not well defined. The preventive analgesic effect of acetaminophen has yet to be quantified in a meta-analysis. The objective of the current investigation was to evaluate the effect of a single preventive dose of systemic acetaminophen on postoperative pain outcomes.A wide search was performed to identify randomized controlled trials that evaluated the effects of a single dose of systemic acetaminophen on pain outcomes in a large variety of surgical procedures. Meta-analysis was performed using a random-effect model.Eleven randomized clinical trials evaluating 740 patients were included in the analysis. The weighted mean difference (95% confidence interval [CI]) of the combined effects favored acetaminophen over control for early pain at rest (≤4 h, −1.1 (−2.0 to −0.2)) and early pain at movement (24 h, −1.9 (−2.8 to −1.0)) Postoperative opioid consumption was decreased in the systemic acetaminophen group compared with control. Weighted mean difference (95% CI) of −9.7 (−13.0 to −6.4) mg morphine intravenous equivalents systemic acetaminophen also reduced postoperative nausea and vomiting compared with control, odds ratio (95% CI) of 0.25 (0.13 to 0.47), numbers needed to treat (95% CI)=3.3 (2.3 to 5.9).Systemic acetaminophen, when used as a single-dose preventive regimen, is an effective intervention to reduce postoperative pain. It also reduces postoperative nausea and/or vomiting. Doses >1 g were not associated with greater reduction in pain outcomes.