In a patient with a particular index disease, the term co-morbidity refers to any additional co-existing ailment. The failure to classify and analyze co-morbid diseases has led to many difficulties in medical statistics. The omissions create misleading data in mortality rates for a general population, and in fatality rates for an individual disease. In particular, neglect of co-morbidity may cause spurious comparisons during the planning and evaluation of treatment for patients with apparently identical diagnoses. Co-morbidity can alter the clinical course of patients with the same diagnosis by affecting the time of detection, prognostic anticipations, therapeutic selection, and post-therapeutic outcome of the index disease. In addition to these direct effects on clinical course, co-morbidity plays a role in intellectual decisions that may alter the statistical categories of diagnostic classification. These decisions deal with the attribution of symptoms in 'polypathic' patients and with the selection of an inception manifestation for the index disease. In order to maintain consistency in the management of research data, certain principles of co-morbid differential diagnosis can be developed according to anatomic relation, pathogenetic interplay, and chronometric features of the diseases under consideration.