There is substantial evidence that physical disability results from chronic diseases and that the number of chronic diseases is associated with the presence and severity of disability. There is some evidence that interactions between specific diseases are of import in causing disability. Beyond arthritis, however, little is known of the disease pairs that may be important to focus on in future research. This study explores the associations between multiple disease pairs and different types of physical disability, with the objective of hypothesis development regarding the importance of disease interactions. The study population comprised a representative sample of 3841 women 65 years and older living in Baltimore, screened for participation in the Women's Health and Aging Study. The study design was cross-sectional. An interviewer-administered screening questionnaire was administered regarding self-reported physical disability in 15 tasks of daily life, history of physician diagnosis of 14 chronic diseases, and MiniMental State examination. Task difficulty was empirically grouped into six subsets of minimally overlapping disabilities, with a comparison group consisting of those with no difficulty in any task subset. Multiple logistic regression models were fit assessing the relationship of major chronic diseases and of interactions of disease pairs with each disability subtype and with any disability, adjusting for confounders. Fourteen percent of the population reported mobility difficulty only; 5%, upper extremity difficulty only; 9%, both of these difficulties but no others; 7%, difficulty in higher function but not self-care tasks; 7%, self-care task difficulty but not higher function tasks; and 15%, difficulty in both higher function and self-care (weighted data). Almost all in the latter three groups had difficulty, as well, in mobility or upper extremity tasks. In regression models, specific disease pairs were synergistically associated with different types of disability. For example, important disease pairs that recurred in their associations with different disability types were the presence of arthritis and visual impairments, arthritis and high blood pressure, heart disease and cancer, lung disease and cancer, and stroke and high blood pressure. In addition, the type of disability that a disease was associated with varied, depending on the other disease that was present. Finally, when interactions were accounted for, many diseases were no longer, in themselves, independently associated with a given type of disability. Partitioning disability into six subtypes was more informative in terms of associations than was evaluating a summary category of "any disability." These findings provide a basis for further hypothesis development and testing of synergistic relationships of specific diseases with disabilities. If testing confirms these observations, these findings could provide a basis for new strategies for prevention of disability by minimizing comorbid interactions.