Sedentary behavior, particularly in prolonged periods, is an important determinant of health. Little research exploring changes in sedentary behavior during behavioral weight loss programs exists. This study evaluated the magnitude of changes in total and prolonged sedentary behavior and how these changes related to changes in weight and cardiovascular outcomes during a behavioral weight loss program. Participants (n = 450) in two lifestyle modification programs underwent assessments of sedentary behavior (by accelerometry), weight, waist circumference, blood pressure, and resting heart rate at baseline and after 6 months of treatment. Sedentary behavior was defined as both total and prolonged (≥30 continuous minutes) sedentary minutes/day. Reductions in total and prolonged sedentary time were significant and were accounted for by increases in moderate-to-vigorous physical activity (MVPA). Only changes in MVPA significantly predicted change in weight when entered into a model simultaneously with changes in sedentary behavior. Changes in total and prolonged sedentary time were not associated with changes in waist circumference, heart rate, or blood pressure. Change in sedentary time was not independently associated with change in health outcomes during a behavioral weight loss treatment. High variability in changes in sedentary time indicate that individual differences may be important to examine. Reducing sedentary time may not be powerful enough to impact these health outcomes above the effects of other changes made during these programs; alternatively, it may be that increasing focus in treatment on reducing sedentary time may engender greater decreases in sedentariness, which could lead to better health outcomes.