Background Workers in certain occupations may have elevated risks of psychological distress. However, research is limited. For example, researchers often measure distress that may have existed before occupational exposures. We studied occupations and the development of psychological distress using national data from the United States. Methods We reviewed relevant research to identify occupations with low and high risks of mental health problems. We confirmed those individual low and high risk occupations using 1981–2017 data from the Panel Study of Income Dynamics (n = 24,789). We measured new cases of distress using the Screening Scale for Psychological Distress (Kessler K6) and compared distress in the low and high risk groups, adjusted for factors associated with occupational selection and non-occupational distress risks. A subset of participants described their jobs (n = 1,484), including factors such as job demands, social support, and control over work. We examined associations of those factors with psychological distress. Results Workers in high risk occupations had 20% higher adjusted odds of developing distress than those in low risk occupations (odds ratio, OR 1.20, 95% confidence interval, CI 1.13 - 1.28). Distress increased with time in a high risk occupation: greater than or equal to 5 years OR 1.38 (CI 1.18 - 1.62), greater than or equal to 10 years OR 1.46 (CI 1.07 - 1.99), and greater than or equal to 15 years OR 1.77 (CI 1.08 - 2.90; p-trend = 0.0145). The most common positive participant descriptions of their jobs indicated social support (34%), sense of accomplishment (17%), and control over work (15%). Participants reporting such descriptions were significantly less likely to have a high risk occupation (OR 0.66, CI 0.46 - 0.94, p = 0.0195). The most common negative descriptions were excessive job demands (43%), low social support (27%), and lack of control (14%). Participants reporting such descriptions were significantly more likely to have a high risk occupation (OR 1.49, CI 1.03 - 2.14, p = 0.0331). Conclusion Certain occupations may have high risks of psychological distress, which may be due to characteristics of the occupations rather than employee characteristics, or in addition to them. Results were consistent with theoretical models of psychosocial work environments. Providers of health care and social services should ask patients or clients about work-related distress.