Moderate and severe obesity (BMI ≥35 kg/m2) affect 15% of US adults, with a projected increase over the next two decades. This study reviews evidence of behavioral lifestyle interventions for weight loss in this population. We searched PubMed, PsychInfo, CINAHL®, and Scopus through February 2016 for experimental and quasi-experimental studies that tested a dietary and/or physical activity intervention with a behavioral modification component versus a comparator; and had ≥six-month follow-up and a weight-related primary outcome. Twelve studies representing 1,862 participants (mean BMI 37.5–48.3, mean age 30–54 years) were included. Nine studies compared different behavioral interventions and three tested behavioral intervention(s) versus pharmacological or surgical treatments. Among the 25 behavioral interventions in the 12 studies, 18 reported percent of participants achieving clinically significant weight loss up to 12 months (32–97% achieving 5% or 3–70% achieving 10%). Three studies measured other cardiometabolic risk factors, but showed no significant risk reduction. Seven interventions with greater effectiveness (i.e., at least 31% achieving ≥10% or 62% achieving ≥5% weight loss up to one year) included multiple components (diet, physical activity, and behavioral strategies), long duration (e.g., one year), and/or intensive contacts (e.g., inpatient stays for clinic-based interventions, weekly contacts for community-based ones). Evidence for the effectiveness of behavioral interventions versus pharmacological or surgical treatment was limited. Comprehensive and intensive behavioral interventions can result in clinically significant, albeit modest, weight loss in this obese subpopulation but may not result significant improvements in other cardiometabolic risk factors. More research on scalable and sustainable interventions is needed.