Since obesity is the second leading cause of preventable death in the United States, effective treatments are crucial in order to stop the progression of this epidemic. Currently, orlistat (Xenical) and sibutramine (Meridia, Reductil) are the only FDA approved obesity drugs for long-term weight loss in adults. The aim of this study is to compare the effectiveness of these two drugs in initial weight loss as well as long-term maintenance of that weight lost. An evidence-based systematic literature review was conducted using the following databases: Medline, ECO, and Cochrane. Articles chosen for inclusion were from 1990 to present, level 1 or 2 evidence and from peer-reviewed journals. Participants were over 18 years old with a BMI greater than 27 kg/m2. There were 18 level 1 randomized controlled trials demonstrating the effectiveness of both medications to produce weight loss. Therefore, a Grade A recommendation can be made regarding the use of either orlistat or sibutramine in a primary care setting for 5-10% weight loss. Also, there were 10 level 1 randomized controlled trials demonstrating the management of the weight loss for up to 2 years, so a Grade A recommendation can be made regarding the use of either orlistat or sibutramine in the long-term management of weight loss. Both medications are effective for an obese patient who has failed on diet and exercise alone, so selection of which medication to prescribe is primarily determined on which medication the patient is most able to tolerate.