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Purpose: To systematically compare the efficacy and safety of sufentanil versus fentanyl for pain relief in labor involving combined spinal-epidural analgesia (CSEA), a systematic review and meta-analysis of randomized controlled trials targeting parturients requesting labor analgesia was conducted. Methods: The primary outcome measure was visual analog scale scores assessed at 10, 15, 30, and 60 min after intrathecal injection. Secondary outcomes included duration of spinal analgesia, incidence of side effects in parturients, and neonatal Apgar scores. Results: Twelve randomized controlled trials, including data from 881 patients fulfilled the inclusion criteria. No clinically meaningful differences in pain reduction after intrathecal injection were found between the two analgesics. Sufentanil extended the duration of spinal analgesia by 25.40 min (95% CI 21.82 to 28.98 min; p < 0.00001) compared with fentanyl. The risk for pruritus, nausea, and vomiting among parturients was 82% for those using sufentanil (relative risk 0.82 [95% CI 0.67–0.99]; p = 0.04) and 48% for those using fentanyl (relative risk 0.48 [95% CI 0.29–0.80]; p = 0.005). Both the synthesis results and sensitivity analysis demonstrated no differences in the risk for respiratory depression between parturients using sufentanil versus fentanyl. The neonates in sufentanil group exhibited higher Apgar scores than the fentanyl group 5 min after delivery (weighted mean difference 0.10 [95% CI 0.05–0.16]; p = 0.0002). Conclusion: Existing evidence suggests that compared with fentanyl, sufentanil used for analgesia in combined spinal-epidural during labor is more effective in extending the duration of spinal analgesia, and may be safer for the infant. There was overall low clinical and statistical heterogeneity among the included studies. For all outcomes, variations caused by heterogeneity across trials were acceptable. Thus the findings of this meta-analysis may provide additional evidence for future clinical practices of pain relief in labor involving CSEA. Stronger evidence supporting this conclusion will require data from more high-quality and multicenter randomized controlled trials. [ABSTRACT FROM AUTHOR]