BACKGROUND: /st>Over a 5 yr period, we have encountered three patients in whom remifentanil appeared to have no clinical effect during general anaesthesia (GA). We describe seven anaesthetics in these three patients. METHODS: /st>We reviewed the literature on this subject. A simple reproducible test to explore this response was designed. This involved a controlled infusion of increasing doses of remifentanil while observing respiratory variables, pain threshold, pupil size, and Glasgow coma scale score. In addition, blood was sampled for genotyping. RESULTS: /st>No description of this impaired response was found in the review of the literature. Two of the patients agreed to participate in the test. In both patients, we found a seemingly normal analgesic response but a lack of respiratory depression and almost no depression of consciousness, even at doses well above the recommended level for clinical use. The genotyping did not explain the results of the test. CONCLUSIONS: /st>The potential causes of this effect are discussed. We advise clinicians to be aware of this unusual response to remifentanil. If such a response is suspected, we recommend the use of another opioid. If this is suspected before GA, we propose the use of our test as a diagnostic tool.