The ability of midazolam, a benzodiazepine, to reduce the distress associated with lumbar puncture and bone marrow aspiration was examined in 23 children with acute lymphocytic leukemia. Patients were randomized to receive 0.2 mg/kg midazolam HCl or placebo intravenously 3-5 min before the procedures, under double-blind conditions. Based on prior experiences, children in both groups anticipated severe pain from these procedures. Postprocedure pain ratings by patients were markedly reduced in the midazolam but not the placebo group. Both physicians and parents judged the midazolam group as significantly less distressed than controls during and after the procedures. Trained observers recorded significantly fewer pain- and anxiety-related behaviors in the midazolam group immediately before and after, but not during the procedures. The amnestic effects of midazolam, confirmed in a visual recall/recognition test, appear to account for the decreased pain ratings since the behavioral manifestations were similar in the two groups. There were no adverse drug reactions or significant changes in vital signs. Midazolam warrants further investigation as a premedication for painful diagnostic and treatment procedures in children with cancer.