BACKGROUND The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may thereby prevent cardiac complications. OBJECTIVE This review assessed the efficacy and safety of preoperative (within 24 hours), intraoperative, and postoperative (first 48 hours) alpha-2 adrenergic agonists for preventing mortality and cardiac complications after surgery performed under either general or neuraxial anaesthesia, or both. METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to August week 4 2008), EMBASE (1980 to week 36 2008), the Science Citation Index, and reference lists of articles. METHODS We included randomized controlled trials that compared alpha-2 adrenergic agonists (clonidine, dexmedetomidine, or mivazerol) against placebo or non-alpha-2 adrenergic agonists. Included studies had to report on mortality, myocardial infarction, myocardial ischaemia, or supraventricular tachyarrhythmia. METHODS Three authors independently assessed trial quality and extracted data. Two authors independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. RESULTS We included 31 studies (4578 participants). Study quality was generally inadequate, with only six studies clearly reporting methods for blinding and allocation concealment. Overall, alpha-2 adrenergic agonists reduced mortality (relative risk (RR) 0.66; 95% CI 0.44 to 0.98; P = 0.04) and myocardial ischaemia (RR 0.68; 95% CI 0.57 to 0.81; P < 0.0001). However, their effects appeared to vary with the surgical procedure. The most encouraging data pertained to vascular surgery, where they reduced mortality (RR 0.47; 95% CI 0.25 to 0.90; P = 0.02), cardiac mortality (RR 0.36; 95% CI 0.16 to 0.79; P = 0.01), and myocardial infarction (RR 0.66; 95% CI 0.46 to 0.94; P = 0.02). With regard to adverse effects, alpha-2 adrenergic agonists significantly increased perioperative hypotension (RR 1.32; 95% CI 1.07 to 1.62; P = 0.009) and bradycardia (RR 1.66; 95% CI 1.14 to 2.41; P = 0.008). CONCLUSIONS Our study provides encouraging evidence that alpha-2 adrenergic agonists may reduce cardiac risk, especially during vascular surgery. Nonetheless, these data remain insufficient to make firm conclusions about their efficacy and safety. A large randomized trial of alpha-2 adrenergic agonists is therefore warranted. Additionally, future research must determine which specific alpha-2 adrenergic agonist should be used, and whether it is safe to combine them with other perioperative interventions (for example beta-adrenergic blockade).