In 2006, the Institute of Medicine (IOM) released Ethical Considerations for Research Involving Prisoners. This federal report recommends long-overdue changes to the federal regulations that limit human subjects research on prisoners. First, the Report recommends more systematic and rigorous review of all experimentation involving prisoners and other persons supervised under any form of state or federal custody. Second, the Report recommends implementing a flexible, risk-benefit analysis to evaluate proposed experiments on prisoners, in place of current federal regulations, which categorically exclude prisoners from many forms of experimentation. This Comment represents the first careful legal analysis of the 2006 IOM Report’s recommendations regarding prisoner experimentation. Investigative research reveals that medical experimentation currently takes place in prisons across the United States, in spite of federal regulations implemented in the 1970s in order to curtail such experimentation. Furthermore, an analysis of modern standards regulating experimentation on prisoners, from across the world and throughout U.S. courts, suggests that current protections for U.S. prisoner subjects of experimentation are inadequate. This Comment argues that the calls for greater oversight of prisoner experimentation in the 2006 IOM Report represent a necessary and welcome reform. However, the suggested risk-benefit framework for evaluating future experimental protocols fails to account for current prison conditions and does not provide adequate protections to prisoners. Therefore, the federal government should not implement this risk-benefit framework.