The 5-HT(3) antagonists tropisetron and granisetron have been shown to block the analgesic effect of acetaminophen in healthy volunteers. To study the interaction between ondansetron and acetaminophen in women undergoing laparoscopic hysterectomy, we randomized 134 patients into three groups to receive acetaminophen-placebo (AP), acetaminophen-ondansetron (AO), or placebo-placebo (PP). One gram of intravenous acetaminophen or placebo was administered at the induction of anesthesia and every 6 h thereafter for 24 h, and 4 mg of ondansetron or placebo was administered at the end of surgery. Pain control was provided by patient-controlled analgesia (PCA)-oxycodone. Acetaminophen (as compared to placebo) in periodic doses starting at induction of anesthesia reduced the total dosage of oxycodone required over 0-24 h (P = 0.031), but ondansetron given at the end of the surgery had no impact on the analgesic effect of acetaminophen (P = 0.723). The Numeric Rating Scale (NRS) scores for pain were similar whether ondansetron or placebo was administered at the end of the surgery. Therefore, it may be concluded that in women undergoing laparoscopic hysterectomy, the administration of periodic doses of intravenous acetaminophen (as compared to placebo) starting at induction of anesthesia reduces the total dose requirement of oxycodone, and a concomitant dose of a 5-HT(3) antagonist such as ondansetron at the end of the surgery does not block the analgesic effect of acetaminophen.