We investigated the efficacy of a combination of ketamine and midazolam, comparing intravenous, oral, and rectal administrations for invasive procedures in children with malignancy. Seventy-three children under 5 years of age, who were scheduled for invasive procedure, were assigned to one of three groups: IV group (n=25), ketamine 1 mg/kg and midazolam 0.05-0.1 mg/kg were given intravenously; PO group (n=24), ketamine 3 mg/kg and midazolam 0.5 mg/kg were given orally; and PR group (n=24), ketamine 3 mg/kg and midazolam 0.5 mg/kg given rectally. Vital signs including blood pressure, pulse rate, respiratory rate, and oxygen saturation were monitored, and patients were observed for side-effects. Optimal sedation (drowsy and asleep) was provided in 78 per cent of all patients and no statistical difference was observed among the three groups. No severe complications were observed in all groups. Recovery time from sedation was significantly longer in the intravenous group (>120 min in two patients). Hallucination was noted in three (12 per cent) patients given intravenous medication, but not in those given oral or rectal medications. It is concluded that intravenous, oral, and rectal midazolam/ketamine are equally effective for invasive procedures in children with malignancy. The use of intravenous ketamine/midazolam may produce prolonged sedation and psychedelic effects in children. These adverse effects may alter the child's comfort and parental satisfaction.