The aim of this study was to explore what employees with severe medically unexplained physical symptoms (MUPS) experience as causes of distress with regard to employees with mild or no MUPS. Methods: This study is an additional analysis of a cross-sectional study in which 486 sick-listed employees, were assessed with Patient Health Questionnaire (PHQ)-15 for self-rated levels of MUPS. A cutoff score of 15 (≥15) was used to categorise employees with severe MUPS. Distress was qualitatively categorised with the answers on the open question in the PHQ-15 "if you experience distress at this moment, what are you distressed about?" Results: Sick-listed employees with severe MUPS were most distressed by their medical, mental, and financial problems. Employees with mild or no MUPS by their medical, work-related, and return to work-related problems. Employees with severe MUPS had more often distress by their mental and financial problems, compared to the employees with mild and no MUPS, who had more often no problems. Conclusions: There are differences in the causes of distress in sick-listed employees with severe MUPS compared to those with mild or no MUPS. Exploring these causes create possibilities for the physician to improve the quality of explanations and reassurance to the employee and to remove barriers for the return to work process.