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The aim of this study was to conduct a meta-analysis and systematic review of randomized controlled trials (RCTs) comparing 2 methods of colonic insufflation for elective colonoscopy, that is, carbon dioxide (CO2) or air, and to evaluate their efficiency, safety, and side effects.Prospective RCTs comparing CO2 versus air insufflation for colonic distension during colonoscopy were selected by searching PubMed, Medline, Embase, Science Citation Index, Current Contents, and the Cochrane Central Register of Controlled Trials published between January 1980 and October 2014.The outcome variables analyzed included procedural and immediate postprocedural pain (during, end, or within 15 min after procedure), early postprocedural pain (between 30 and 120 min), intermediate postprocedural pain (360 min) and late postprocedural pain (720 to 1140 min), cecal/ileal intubation rate, cecal/ileal intubation time, and total colonoscopy examination time. These outcomes were unanimously decided to be important as they influence the practical approach toward patient management within and outside of hospital. Random effects model was used to calculate the effect size of both binary and continuous data. Heterogeneity among the outcome variables of these trials was determined by the Cochran Q statistic and I2 index. The meta-analysis was prepared in accordance with PRISMA guidelines.Twenty-four RCTs totaling 3996 patients (CO2=2017, Air=1979) were analyzed. Statistically significant differences for the pooled effect size were observed for procedural and immediate postprocedural pain [weighted mean difference (WMD)=0.49; 95% confidence interval (CI), 0.32, 0.73; P=0.0005], early postprocedural pain between 30 and 120 minutes (WMD=0.25; 95% CI, 0.12, 0.49; P<0.0001), intermediate postprocedural pain, that is, 360 minutes after completion (WMD=0.35; 95% CI, 0.23, 0.52; P<0.0001), and late postprocedural pain between 720 and 1440 minutes (WMD=0.53; 95% CI, 0.34, 0.84; P=0.0061). Comparable effects were noted for cecal/ileal intubation rate (WMD=0.86; 95% CI, 0.61, 1.22; P=0.3975), cecal/ileal intubation time (WMD=−0.64; 95% CI, −1.38, 0.09; P=0.0860), and total examination time (WMD=−0.20; 95% CI, −0.96, 0.57; P=0.6133).On the basis of our meta-analysis and systematic review, we conclude that CO2 insufflation significantly reduces abdominal pain during and following the procedure lasting up to 24 hours. There is no difference in the cecal/ileal intubation rate and time and total examination time between the 2 methods. CO2 retention with CO2 insufflation during and after the colonoscopy shows inconsequential variation compared with air insufflation and has no adverse effect on patients. CO2 instead of air should be routinely utilized for colonoscopy.