One of the Healthy People 2020 national objectives is to increase the prevalence of a healthy weight among adults to 34% and to reduce the prevalence of obesity among adults to less than 30%. From 2005 to 2008, only 31% of adults were a healthy weight. Obesity was estimated to cost $79 billion in the U.S. during 1995. By 2008, health care costs associated with obesity were thought to have risen to $147 billion. The Federal Government pays about one half of these costs through Medicaid and Medicare spending. Body mass index (BMI)-expressed as weight in kilograms divided by height in meters squared (kg/m2)-is commonly used to classify underweight (BMI less than 18.5 kg/m), healthy or normal weight (BMI 18.5-24.9 kg/m), overweight (BMI 25.0-29.9 kg/m), obesity (BMI greater than or equal to 30.0 kg/m), and extreme obesity (BMI greater than or equal to 40.0 kg/m). Adults tend to gain weight progressively through middle age. Although the average weight gained per year is 0.5 to 1 kg, the modest accumulation of weight over time can lead to obesity. The estimated age-adjusted prevalence of overweight and obesity (BMI greater than or equal to 25.0 kg/m) was 68% in the U.S. during 2007 and 2008. Despite the doubling in the prevalence of obesity between 1976 and 1980 and 2007 to 2008 (13 to 34%), the prevalence of overweight has remained stable between the same time periods (32 to 34%). Obesity is a risk factor for chronic conditions including cardiovascular disease, type 2 diabetes, arthritis, certain types of cancer, and cancer recurrence. Weight is associated with an increased risk of some forms of cancer and cancer recurrence. There is growing evidence that breast cancer survivors or women with breast cancer have better outcomes if they lose or maintain their weight. Obesity can also be caused by medications used to treat chronic disease, as is the case for antipsychotic treatments, some treatments for type 2 diabetes, and tamoxifen and aromatase inhibitors for treatment or prevention of breast cancer or cancer recurrence. Higher grades of obesity are associated with excess mortality, primarily from cardiovascular disease, type 2 diabetes, and certain types of cancer. We aimed to review studies of strategies to prevent weight gain among adults. The strategies of interest were self-management techniques, diet, physical activity, use of the dietary fat absorption inhibitor orlistat, or combinations of these strategies applied at the individual, community, or environment level. These strategies could have been implemented in any setting, including clinical care sites, community settings, higher education institutions, and workplaces. Strategies could have targeted individuals at high risk of gaining weight because of a family history of obesity or diabetes mellitus, personal risk factors for diabetes mellitus and cardiovascular disease (such as borderline values of laboratory measures), use of medication associated with weight gain, or have had more inclusive enrollment criteria. We aimed to compare the effectiveness, safety, and impact on quality of life of independent and combined strategies to prevent weight gain among adults. The specific Key Questions are: KQ1: What is the comparative effectiveness of self-management KQ2: strategies for the prevention of weight gain among adults? What is the comparative effectiveness of dietary KQ3: strategies for the prevention of weight gain among adults? What is the comparative effectiveness of physical activity KQ4: strategies for the prevention of weight gain among adults? What is the comparative effectiveness of orlistat KQ5: for the prevention of weight gain among adults? What is the comparative effectiveness of a combination KQ6: of self-management, dietary, physical activity, and orlistat strategies for the prevention of weight gain among adults? What is the comparative effectiveness of environment-level strategies for the prevention of weight gain among adults?