Background. This study describes the differences in psychological distress, disability and psychosocial resources between types of major medical conditions and sensory impairments (collectively denoted as CMCs); and tests whether disability and psychosocial resources mediate CMC-specific mental health effects. Methods. Data were obtained from a population-based, cross-sectional survey of 5078 non-institutionalized, late middle-aged and older Dutch persons. The predictors were 16 types of CMCs, including all major chronic medical diseases as well as impairment of hearing, vision, and cognition. The outcomes were assessed in terms of psychological distress as measured by the Hospital Anxiety and Depression Scale. Two aspects of disability were measured (namely, physical and role functioning) and also three psychosocial resources (namely, mastery, self-efficacy and social support). Results. Level of psychological distress varied across type of CMC. Hearing impairment, neurological disease, vision impairment, and lung and heart disease had particularly strong associations with distress. The level of distress in patients with hearing impairment was 0.45 standard deviation higher than in those without hearing impairment (adjusted for demographics and all other CMCs). Roughly similar patterns of association were found between type of CMC and disability, and also, but to a lesser extent, mastery and self-efficacy. Stepwise multiple regression revealed that type of CMC accounted for 9% of the variance in distress initially, but this fell to 1% after the variance due to disability, mastery and self-efficacy was taken out. Social support was not a mediator. Disability and psychosocial resources accounted for 13% and 14% of the variance in distress, respectively. Conclusion. These results support the conventional wisdom that it is not the nature of the condition that determines psychological distress, but instead the severity of the disability and loss of psychological resources associated with the condition on the one hand and the psychological characteristics of the patient on the other.