Burnout and prolonged fatigue have hardly been compared empirically despite their similarities. Knowledge on bow these conditions influence each other in time is limited, although this could have implications for (the timing of) intervention. This study examined the temporal relationship between burnout and prolonged fatigue Four-year prospective follow-up data from the Maastricht Cohort Study were used for this study. After selection, 11,710 of the 12,140 participants could be included. Measures included the Maslach Burnout Inventory-General Survey and the Checklist Individual Strength. Data were analysed using Cox regression analysis, generalized estimating equation analysis and multinomial regression analysis. Adjustments at baseline were made for burnout or prolonged fatigue score, age, gender, education and absenteeism at baseline. Burnout at baseline was associated with an increased risk of subsequent prolonged fatigue (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.16-1.53) and prolonged fatigue was associated with an increased risk of subsequent burnout (HR 1.65, 95% CI 1.44-1.89). When burnout and prolonged fatigue influence each other in time, they tend to co-occur rather than replace each other. Burnout and prolonged fatigue seem to influence each other in the manner of a 'downward spiral'. Recognizing and correctly identifying fatigue complaints related to burnout and/or prolonged fatigue at an early stage seems important, as early intervention could prevent the conditions from co-occurring and avert a worsening of outcome.