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There is substantial controversy regarding the current evidence basis of practice for neurophysiologic intraoperative monitoring (NIOM). The randomized controlled trial is clearly the highest level of evidence of efficacy for intervention in health care. The low rate of new neurologic deficits in many types of surgeries for which NIOM is considered means that statistical power would require tremendous trial size; however, there are some surgeries with higher rates of new neurologic deficit for which this effect is not the case. For some surgeries, NIOM has clearly become the standard of care, and there would be no equipoise in randomization to NIOM versus no NIOM at all. For this situation, careful study design to permit comparison of different NIOM approaches or anesthesiological regimens might permit the achievement of equipoise. In oncological contexts, NIOM is often used to delimit the extent of resection to avoid motor new neurologic deficits, but this approach may lower complete resection rates; in this setting, a randomization to restrictive versus permissive NIOM parameters limiting resection could test the long-term advantages of motor versus oncological outcomes. Clearly, randomized controlled trial demonstration of NIOM efficacy for the prevention of new neurologic deficits would be difficult to accomplish. However, with careful choice of surgical population and randomization design, prospective trials would in fact not be impossible.