Phase I trials are increasingly including dose-expansion cohorts after the maximum-tolerated dose (MTD) has been reached to better characterize the toxicity profile or identify early signs of efficacy within a specific disease population. This article provides guidelines on how to monitor safety and re-evaluate the MTD using data obtained from expansion cohorts of phase I protocols. We illustrate how to implement a sequential monitoring rule for safety using a completed phase I trial that included an expansion cohort. We compare the accuracy of the revised MTD with the MTD obtained before expansion and with the true MTD based on simulated trials. The percent of trials that led to a change in the MTD, how far the revised MTD was from the true MTD, and the toxicity rates associated with each level are reported. When toxicity outcomes from the expansion cohort are taken into account, there is a 50% chance that a new, higher MTD will be recommended. Significant improvement in the accuracy of the MTD is obtained 30% of the time (ie, revised MTD is exactly the true MTD), and moderate improvement is obtained 80% of the time when the revised MTD is within a level from true MTD. Failure to include toxicity outcomes from additional patients treated during the expansion phase may result in a less accurate estimate of the MTD. This article provides investigators of phase I protocols with methodological tools to monitor safety and/or efficacy for patients accrued during the expansion phase and to update or confirm the established MTD.