Prospective clinical trials are the gold standard for evidence-based methodology used to support changes in the practice of medicine. Clinical researchers, regulatory agencies, payers, and the public embrace the conduct of phase I, II, and III clinical trials as integral to improving patient care. The National Cancer Institute (NCI) funds a number of cooperative oncology groups to conduct such clinical trials in the United States. In order to protect enrolling patients, the NCI requires expedited reporting to allow rapid identification of severe side effects on NCI-sponsored clinical trials. However, chemotherapy drugs frequently cause predictable side effects, the rapid reporting of which would potentially overwhelm the system. This article describes the development and documents the performance of a real-time toxicity reporting system implemented by the North Central Cancer Treatment Group. The goal of this system is to supplement the currently required NCI adverse event monitoring procedures and to permit study teams to identify the need to modify ongoing clinical trials. The system has proven its value in the monitoring of phase II and III trials, including trial N9741, a three-arm, phase III, advanced colorectal cancer chemotherapy study exploring combinations of irinotecan, oxaliplatin, and fluorouracil. We believe the methods described present opportunities for improving patient safety in clinical research.