Objective To systematically assess the effectiveness and safety of 5-HT3 receptor antagonists in preventing propofol injection induced pain. Methods Databases including PubMed, EMbase, The Cochrane Library (Issue 1, 2012), CNKI, CBM, VIP and WanFang Data were searched from their inception to September, 2012 to collect the randomized controlled trials (RCTs) about 5-HT3 receptor antagonists in preventing propofol injection induced pain. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted the data, and assessed the quality of methodology. Then meta-analysis was performed using RevMan 5.2 software. Results A total of 15 RCTs involving 1 413 patients were included. The results of meta-analysis showed that: a) the incidence of propofol injection induced pain in the 5-HT3 group was obviously lower than the control group (RR=0.14, 95%CI 0.09 to 0.21, Plt;0.000 01); b) as to the severity of pain, there was no statistical difference between the two groups (RR=0.84, 95%CI 0.56 to 1.26, P=0.39); the 5-HT3 group was obviously lower that the control group in the incidence of both moderate pain (RR=0.25, 95%CI 0.19 to 0.34, Plt;0.000 01) and severe pain (RR=0.16, 95%CI 0.10 to 0.24, Plt;0.000 01); and c) as to the incidence of postoperative adverse reaction: the 5-HT3 group was obviously lower that the control group in the incidence of nausea and vomiting (RR=0.19, 95%CI 0.11 to 0.34, Plt;0.000 01) and shivering (RR=0.20, 95%CI 0.12 to 0.33, Plt;0.000 01) as well. Conclusion 5-HT3 receptor antagonists can effectively prevent the propofol injection induced pain, alleviate its severity, and reduce the postoperative adverse reactions. For the quantity and quality limitation of the included studies, this conclusion still needs to be further proved by performing more high quality studies.