Background: The Committee for Medical Ethics (CME) of Leiden University Medical Center (LUMC) was established as the first medical ethics reviewing committee (MREC) in the Netherlands. In the period 2000–2010 the CME received 2,162 protocols for review. Some of these protocols were never approved. Until now, there has existed neither an overview of these failed protocols nor an overview of the reasons for their failure. Methods: This report draws on data from the digital database, the physical archives, and the minutes of the meetings of the CME. Additional information has been obtained from the Central Committee on Research involving Human Subjects (CCRH) and survey-based research. Protocols were itemized based on characteristic features and their reviewing procedures were analyzed. Results: In total, 1,952 out of 2,162 research protocols submitted during 2000–2010 (90.3%) were approved by the CME; 210 of 2,162 protocols (9.7%) were not approved. Of these 210 protocols, 177 failed due to reasons not related to CME reviewing. In 15 cases CME reviewing led to protocol failure, while another 10 protocols were rejected outright. Eight of the 210 submitted protocols without approval had been conducted prior to submission. Conclusions: In the aforementioned period, little protocol failure occurred. For the most part, protocol failure was caused by problems that are not CME related. This type of failure has several identifiable factors, none of which have anything to do with the ethical reviewing procedure by the CME. A mere 1.2% of protocols failed due to ethical review. Unacceptable burden and risks to the subject and an inadequate methodology are the most common reasons for this CME-related protocol failure.