BACKGROUND:: Safe and effective alternatives are required in labor when epidural analgesia is not appropriate. We hypothesized that patient-controlled IV remifentanil labor analgesia would not be inferior to patient-controlled epidural labor analgesia. METHODS:: This randomized nonblinded controlled noninferiority study in healthy women with a singleton fetus and vertex presentation was performed at 1 site. Women were randomized to receive patient-controlled IV analgesia titrated from 20 mcg up to a maximum bolus dose of 60 mcg with a lockout interval of 1 to 2 minutes, or patient-controlled epidural analgesia 0.1% bupivacaine with 2 mcg/mL fentanyl (initiation bolus 15 mL; maintenance bolus 10 mL, lockout interval 20 minutes, basal infusion 5 mL/h). Crossover was permitted after 30 minutes. The primary study outcome was efficacy (assessed as hourly numerical rating scale [NRS] pain score [11-point NRS] and maternal satisfaction [11-point NRS]); the secondary outcome was safety (maternal apnea). Supplementary oxygen was administered continuously during the respiratory monitoring period. During the first hour of analgesia, the heart rate, respiratory rate, pulse oximetry (SpO2), and end-tidal CO2, as an indication of apnea, were compared. Apnea lasting >40 seconds was managed by light stimulation by the attending anesthesiologist. RESULTS:: Forty women were recruited to the following groups: remifentanil n = 19 (1 exclusion), epidural n = 20. Four crossed over: 3 from the remifentanil to epidural group and 1 from the epidural to remifentanil group. Mean (± SD) baseline NRS pain scores were similar, 8.4 ± 1.5 for remifentanil and 8.7 ± 1.2 for epidural analgesia, P = 0.52. Baseline adjusted mean NRS reduction at 30 minutes for remifentanil was -4.5 (± 0.6) vs -7.1(± 0.6) for epidural analgesia, P < 0.0001 for both. Pain score at 30 minutes was 3.7 ± 2.8 for remifentanil and 1.5 ± 2.2 for epidural analgesia, P = 0.009. Remifentanil was inferior to epidural analgesia with respect to the NRS at all time points, because the observed difference in NRS was greater than the expected -1.5 units. Maternal satisfaction was 8.6 ± 1.4 for the remifentanil group and 9.1 ± 1.5 for epidural group, P = 0.26. Mean respiratory rate was lower in the remifentanil group, 18 ± 4 vs 21 ± 4 breaths/min in the epidural group, P = 0.03. Mean SpO2 was lower in the remifentanil group 96.8% ± 1.4 vs 98.4 ± 1.2 for epidural group, P < 0.0001. There were 9 apnea events; all occurred in 5 women receiving remifentanil (5/19 [26.3%], P = 0.046). Apgar scores and neonatal respiratory outcomes were similar. CONCLUSION:: IV remifentanil is inferior to epidural analgesia for provision of labor analgesia; however, remifentanil does provide a satisfactory level of labor analgesia. Laboring women receiving remifentanil require suitable monitoring to detect and alert for apnea.