Objective: While changes in diet often result in short-term weight loss, weight loss is not typically maintained. It remains unclear why long-term weight loss is so difficult. It was hypothesized that obesity produces persistent changes in behavior that bias animals toward weight regain after weight loss. Methods: Mice were induced to gain weight with a high-fat diet for 6 weeks and then induced to lose this weight with a low-fat diet for 7 subsequent weeks. A control group was maintained on the low-fat diet for all 13 weeks. Activity was measured continuously with home cage activity monitors for the entire experiment. Motivation for sweetened food pellets was tested following weight loss. A separate group of mice was reexposed to a high-fat diet following 2, 4, or 8 weeks of withdrawal to assess the rate of weight regain. Results: Activity levels decreased as animals gained weight and partially recovered following weight loss. Motivation for sucrose pellets was persistently heightened after weight loss. Consistent with these behavioral changes, mice also regained weight at a faster rate when reexposed to a high-fat diet after a period of weight loss. Conclusions: Weight loss after obesity was associated with increased motivation for palatable food and an increased rate of weight regain.