© 2015 American Society for Nutrition. Background: Previous studies suggest that appetite may be dysregulated at low levels of activity, creating an energy imbalance that results in weight gain. Objective: The aim was to examine the relation between energy intake, physical activity, appetite, and weight gain during a 1-y follow-up period in a large sample of adults. Design: Participants included 421 individuals (mean 6 SD age: 27.6 6 3.8 y). Measurements included the following: energy intake with the use of interviewer-administered dietary recalls and calculated by using changes in body composition and energy expenditure, moderate-to-vigorous physical activity (MVPA) with the use of an arm-based monitor, body composition with the use of dual-energy X-ray absorptiometry, and questionnaire-derived perceptions of dietary restraint, disinhibition, hunger, and control of eating. Participants were grouped at baseline into quintiles of MVPA (min/d) by sex. Measurements were repeated every 3 mo for 1 y. Results: At baseline, an inverse relation existed between body weight and activity groups, with the least-active group (15.7 6 9.9 min MVPA/d, 6062 6 1778 steps/d) having the highest body weight (86.3 6 13.2 kg) and the most-active group (174.5 6 60.5 min MVPA/d, 10260 6 3087 steps/d) having the lowest body weight (67.5 6 11.0 kg). A positive relation was observed between calculated energy intake and activity group, except in the lowest quintile of activity. The lowest physical activity group reported higher levels of disinhibition (P = 0.07) and cravings for savory foods (P = 0.03) compared with the group with the highest level of physical activity. Over 1 y of follow-up, the lowest activity group gained the largest amount of fat mass (1.7 6 0.3 kg) after adjustment for change in MVPA and baseline fat mass. The odds of gaining .3% of fat mass were between 1.8 and 3.8 times as high for individuals in the least-active group as for those in the middle activity group. Conclusions: These results suggest that low levels of physical activity are a risk factor for fat mass gain. In the current sample, a threshold for achieving energy balance occurred at an activity level corresponding to 7116 steps/d, an amount achievable by most adults. This trial was registered at clinicaltrials.gov as NCT01746186.