OBJECTIVE Propofol is a new anesthetic agent in clinical practice, but randomized double-blinded prospective studies on its role in pediatric anesthesia remain limited. We aimed to compare the preventive effects of pre-injected lidocaine or ketamine and its pre-mixture on the anesthesia-induced injection pain of propofol using a randomized double-blinded prospective method, and to compare the outcomes with those of medium-/long-chain propofol (M/LCT). METHODS A total of 360 pediatric patients (aged 5-12 years old) who received elective surgery were randomly divided into six groups (n= 60) as follows. S group: control group; L group: lidocaine group; L + P group: lidocaine + propofol group; K group: ketamine group; K + P group: ketamine + propofol group; M group: M/LCT group. After the drug fluid completely entered the cubital vein, the venous access was closed. During propofol injection, the injection pain was scored using the VRS 4-point scale. Meanwhile, the heart rates before and during injection were recorded, the adverse reactions during and after injection were observed, and the incidence rate and degree of pain were evaluated. RESULTS The VRS 4-point scale showed that the incidence rates of injection pain of S group, L group, L + P group, K group, K + P group and M group were 78.3%, 66.67%, 51.66%, 43.33%, 48.33% and 45% respectively. The incidence rates of injection pain of all experimental groups were significantly lower than that of S group (P<0.01). The incidence rates of injection pain of L + P group, K group, K + P group and M group were significantly lower than that of L group (P<0.05). The differences among the other groups were not statistically significant. CONCLUSIONS Intravenous pre-injection of lidocaine, ketamine or those mixed with propofol can all significantly reduce the incidence rate of injection pain of propofol.