Premedication for painful procedures in children with cancer is not routinely used. Many medications used are only intermittently effective or require special equipment or anesthesia support. In a randomized, double-blind, crossover study, the safety and efficacy of midazolam, a short-acting benzodiazepine, were compared with the safety and efficacy of fentanyl, a short-acting narcotic analgesic. In 25 children studied, 100% of children and their parents preferred study drugs to any previous premedication. Seventy-two percent preferred midazolam to fentanyl. Preprocedural anxiety, adverse behavioral symptoms, and visual analog scales all improved and side effects were minimal. It is concluded that premedication for painful procedures should be used routinely in children with cancer. With proper monitoring, fentanyl and midazolam can be used safely in the outpatient clinic setting. Midazolam was found to be the drug of preference for the majority of patients.