Randomized, controlled trials (RCTs) are firmly established as the standard for determining which medical treatments are effective. In some areas of health care, however, among them surgery, public health, and the organization of health care delivery, most evidence addressing the effectiveness of clinical or policy interventions rests on nonrandomized studies. We examine the use of study designs other than RCTs in Evidence-based Practice Center reports addressing questions of the effectiveness of treatment interventions. These reports offer the opportunity to examine the approaches used and the challenges faced by reviewers when nonrandomized studies are included and their quality assessed. We then offer recommendations for using these studies in systematic reviews of treatment interventions.