Background: Overweight and obesity are important predictors of a wide variety of health problems. Analysis of naturally occurring changes in body weight can provide valuable insights in improving our understanding of the influence of demographic, lifestyle, and psychosocial factors on weight gain in middle‐age adults.Objective: To identify gender‐specific predictors of body weight using cross‐sectional and longitudinal analyses.Methods and Procedures: Anthropometric, lifestyle and psychosocial factors were measured at baseline and then quarterly for 1 year in 572 healthy adult volunteers from Central Massachusetts who were recruited between 1994 and 1998. Linear mixed models were used to analyze the relationship between body weight and potential predictors, including demographic (e.g., age, educational level), lifestyle (e.g., diet, physical activity, smoking), and psychosocial (e.g., anxiety, depression) factors.Results: Over the 1‐year study period, on average, men gained 0.3 kg and women lost 0.2 kg. Predictors of lower body weight at baseline in both men and women included current cigarette smoking, greater leisure‐time physical activity, and lower depression and anxiety scores. Lower body weights were associated with a lower percentage of caloric intake from protein and greater occupational physical activity levels only among men; and with higher education level only among women. Longitudinal predictors of 1‐year weight gain among women included increased total caloric intake and decreased leisure‐time physical activity, and among men, greater anxiety scores.Discussion: Demographic, lifestyle and psychosocial factors are independently related to naturally occurring changes in body weight and have marked differential gender effects. These effects should be taken into consideration when designing interventions for weight‐loss and maintenance at the individual and population levels.