Previous studies of personality and health have focused mainly on the influence of psychological factors on single diseases such as cancer and coronary heart disease (CHD), thereby neglecting the problem of comorbidity (i.e. the combination of different diseases). The main focus of the present study was the discrimination between single- and multiple-disease conditions on the basis of personality traits. An extensive battery of personality scales implicated in health was administered to a sample of n=5133 individuals of both genders between the ages of 40 and 65. Subjects also reported their health or illness status. A factor analysis of the personality scales yielded five dimensions clearly interpretable as “Emotional Lability”, “Type A Behaviour”, “Behavioural Control”, “Locus of Control over Diseases”, and “Psychoticism”. Hierarchical cluster analyses of the subsample of participants who reported suffering from more than one disease led to eight clusters representing individuals with different combinations of diseases. Generally, there were very few significant differences between healthy and single-disease participants with regard to personality. However, mean factor scores calculated for “Emotional Lability” were higher across the multiple-disease groups than in the healthy and single-disease groups. No other personality factor showed this trend. In general the results reported here show the important role negative affectivity (e.g. Emotional Lability, Neuroticism, Depression) plays in differentiating between single and multiple diseases. Copyright © 2003 John Wiley & Sons, Ltd.