The association of psychosocial stress with weight gain may have important implications for clinical practice and workplace and public health interventions. To determine whether multiple domains of psychosocial stress were associated with weight gain from 1995 to 2004, the authors analyzed a nationally representative longitudinal cohort of 1,355 men and women in the United States. Change in body mass index was assessed for multiple domains of psychosocial stress related to work, personal relationships, life constraints, and finances, controlling for other factors associated with weight gain. All analyses were stratified by sex and weighted to account for the complex survey design. Among men with high baseline body mass index, weight gain was associated with increasing levels of psychosocial stress related to job-related demands (P < 0.001 for interaction with baseline body mass index), lack of skill discretion (P = 0.014), lack of decision authority (P = 0.026), and difficulty paying bills (P = 0.004). Among women with high baseline body mass index, weight gain was associated with job-related demands (P < 0.001 for interaction with baseline body mass index), perceived constraints in life (P < 0.001), strain in relations with family (P = 0.016), and difficulty paying bills (P = 0.010). Interventions to address psychosocial stress may limit weight gain among overweight and obese men and women.