We conducted a prospective, randomized, double-blind, placebo-controlled trial to examine the efficacy of prophylactic ondansetron on post-operative nausea and vomiting (PONV) during opioid patient-controlled analgesia (PCA). In total, 374 patients using opioid PCA, but otherwise considered to be low risk for PONV, were randomly allocated to ondansetron (4 mg given intravenously and 16 mg added into the PCA pump) or saline (control group). PONV was evaluated in terms of nausea graded on a visual analogue scale, and the number of patients who experienced emetic episodes or needed rescue anti-emetics in the 48-h post-operative period. Patient satisfaction for PCA was scored at the end of the evaluation period. The only difference between the two groups was the higher number of headaches in the ondansetron group. In patients using opioid PCA, but with no other high risk factors for PONV, prophylactic ondansetron does not have any clinical benefit.