Objective: Outcomes in burnout and prolonged fatigue have hardly been compared in longitudinal research, despite several similarities such as the importance of fatigue symptoms in both conditions. This study aims to assess and compare the course of burnout and prolonged fatigue in the working population. Methods: Prospective data from the Maastricht Cohort Study on Fatigue at Work were used. The course was determined in terms of complaints and absenteeism. Participants who completed questionnaires at baseline and at the 12-, 24-, and 48-month follow-ups were divided into three subgroups: "pure fatigue" (n=485), "pure burnout" (n=296), and "burnout & fatigue" (n=426). Results: The "burnout & fatigue" group had the highest proportion (29%) of the chronic course type compared to the "pure burnout" (2%) and "pure fatigue" (9%) groups, in addition to more absenteeism over time compared to the "pure fatigue" group. Recovery from all conditions was highest in the "pure burnout" group (40%). The course of burnout and prolonged fatigue is characterized by its dynamic nature. Discussion: Differences emerged in the course of burnout and prolonged fatigue. The differential diagnosis of employees presenting with fatigue complaints could be important in estimating the outcome of complaints and need for therapy.