Background: Pain is often observed in pediatric patients after craniotomy procedures, which could lead to some serious postoperative complications. However, the optimal formula for postoperative analgesia for pediatric neurosurgery has not been well established. This study aimed to explore the optimal options and formulas for postoperative analgesia in pediatric neurosurgery. Methods: Three hundred and twenty patients aged 1 to 12-years old who underwent craniotomy were randomly assigned to receive 4 different regimens of patient-controlled analgesia. The formulas used were as follows: Control group included normal saline 100ml, with a background infusion of 2ml/h, bolus 0.5ml; Fentanyl group was used with a background infusion of 0.1-0.2 mu g/k.h, bolus 0.1-0.2 mu g/kg; Morphine group was used with a background infusion of 10-20 mu g/kg.h, bolus 10-20g/kg; while Tramadol group was used with a background infusion of 100-400 mu g/kg.h, bolus 100-200g/kg. Postoperative pain scores and analgesia-related complication were recorded respectively. Comparative analysis was performed between the four groups. Results: In comparison of all groups with each other, lower pain scores were shown at 1h and 8h after surgery in Morphine group versus Tramadol, Fentanyl and Control groups (P < 0.05). Both Tramadol and Fentanyl groups showed lower pain scores in comparison to Control group (P < 0.05). Nausea and vomiting were observed more in Tramadol group in comparison to all other groups during the 48h of PCIA usage after operation (P = 0.020). Much more rescue medicines including ibuprofen and morphine were used in Control group (CI = 0.000-0.019). Changes in consciousness and respiratory depression were not observed in study groups. Moderate-to-severe pain was observed in a total of 56 (17.5%) of the study population. Multiple regression analysis for identifying risk factors for moderate-to-severe pain revealed that, younger children (OR = 1.161, 1.027-1.312, P = 0.017), occipital craniotomy (OR = 0.374, 0.155-0.905, P = 0.029), and morphine treatment (OR=0.077, 0.021-0.281, P<0.001) are the relevant factors. Conclusions: Compared with other analgesic projects, PCIA or NCIA analgesia with morphine appears to be the safest and most effective postoperative analgesia program for pediatric patients who underwent neurosurgical operations.