The aim of this study was to achieve a better understanding of the relationship between chronic medical illness and mental distress. Therefore, the association between chronic medical illness and mental distress was analysed, taking into account the modifying effects of generic disease characteristics (concerning course, control and possible stressful consequences), physical quality of life indicators and social and relationship problems. Panel data from the Dutch national Panel of Patients with a Chronic Disease (PPCZ) were used. Data from 1788 chronically medical ill patients (nine disease categories) concerning their mental and physical health have been used in a cross-sectional, multivariate analysis. Somatic disease, generic disease characteristics and physical quality of life were assessed by medical doctors. Mental distress and social/ relationship problems were assessed by questionnaire (respectively, GHQ-12 and Biopro). Members of the panel had more mental distress than a random community sample. However, there were no differences between specific somatic diseases. Relationship, job-related and financial problems increased the probability of mental disorder considerably. Relationship problems may be considered a generic characteristic of chronically ill patients, causing an increased risk of mental disorder. Poor physical health condition contributed to a higher probability of mental disorder as well. General practitioners, home care providers and medical specialists should be aware that people with chronic diseases are in general more at risk of mental disorder. For many chronically ill people, this risk is further exacerbated by social/relationship problems, and a poor level of perceived health.