BACKGROUND: Premedication is considered important in pediatric anesthesia. Benzodiazepines are the most commonly used premedication agents. Clonidine, an alpha2 adrenoceptor agonist, is gaining popularity among anesthesiologists. The goal of the present study was to perform a meta-analysis of studies comparing premedication with clonidine to Benzodiazepines. METHODS: A comprehensive literature search was conducted to identify clinical trials focusing on the comparison of clonidine and Benzodiazepines for premedication in children. Six reviewers independently assessed each study to meet the inclusion criteria and extracted data. Original data from each trial were combined to calculate the pooled odds ratio (OR) or the mean differences (MD), 95% confidence intervals [95% CI] and statistical heterogeneity were accessed. RESULTS: Ten publications fulfilling the inclusion criteria were found. Premedication with clonidine, in comparison with midazolam, exhibited a superior effect on sedation at induction (OR=0.49 [0.27, 0.89]), decreased the incidence of emergence agitation (OR=0.25 [0.11, 0.58]) and produced a more effective early post-operative analgesia (OR=0.33 [0.21, 0.58]). Compared with diazepam, clonidine was superior in preventing post-operative nausea and vomiting (PONV). DISCUSSION: Premedication with clonidine is superior to midazolam in producing sedation, decreasing post-operative pain and emergence agitation. However, the superiority of clonidine for PONV prevention remains unclear while other factors such as nausea prevention might interfere with this result.