The effect of adding clonidine to local anesthetics for nerve or plexus blocks remains unclear. The authors searched for randomized placebo-controlled trials testing the impact of adding clonidine to local anesthetics for peripheral single-injection nerve or plexus blocks in adults undergoing any surgery (except eye) without general anesthesia. Twenty trials (1,054 patients, 573 received clonidine) published 1992-2006 tested plexus (14 brachial, 1 cervical) and nerve blocks (2 sciatic/femoral, 1 midhumeral, 1 ilioinguinal/iliohypogastric, 1 ankle). Clonidine doses ranged from 30 to 300 microg; most patients received 150 microg. Clonidine prolonged the duration of postoperative analgesia (weighted mean difference 122 min; 95% confidence interval [CI] 74-169), sensory block (weighted mean difference 74 min; 95% CI 37-111), and motor block (weighted mean difference 141 min; 95% CI 82-199). In a subgroup of patients receiving an axillary plexus block, these effects were independent of whether clonidine was added to an intermediate or a long-acting local anesthetic. Clonidine increased the risk of arterial hypotension (odds ratio 3.61; 95% CI 1.52-8.55; number-needed-to-harm 11), orthostatic hypotension or fainting (odds ratio 5.07; 95% CI 1.20-21.4; number-needed-to-harm 10), bradycardia (odds ratio 3.09; 95% CI 1.10-8.64; number-needed-to-harm 13), and sedation (odds ratio 2.28; 95% CI 1.15-4.51; number-needed-to-harm 5). There was a lack of evidence of dose-responsiveness for beneficial or harmful effects. Clonidine added to intermediate or long-acting local anesthetics for single-shot peripheral nerve or plexus blocks prolongs duration of analgesia and motor block by about 2 h. The increased risk of hypotension, fainting, and sedation may limit its usefulness. Dose-responsiveness remains unclear.