If schizophrenia is a clinical syndrome rather than a single disease, the identification of specific diseases within the syndrome would facilitate the advance of knowledge and the development of more specific treatments. We propose that deficit psychopathology (ie, enduring, idiopathic negative symptoms) defines a group of patients with a disease different from schizophrenia without deficit features, as the deficit and nondeficit groups differ in their signs and symptoms, course, biological correlates, treatment response, and etiologic factors. These differences cannot be attributed to more severe positive psychotic symptoms or a greater duration of illness in the deficit group. The alternative interpretation that patients with deficit schizophrenia are at the severe end of a single disease continuum is not supported by risk factor and biological features data, but there is a need for independent replication of these findings. We suggest a series of studies designed to falsify one of these hypotheses, ie, multiple diseases vs a single disease.