Individuals with schizophrenia vary widely in their symptoms, course of illness and outcome. Family background is the strongest known risk factor for schizophrenia. We know little of the relationship between clinical variability in this disorder and the level of familial vulnerability to schizophrenia and other major mental disorders. Therefore, in schizophrenic probands meeting DSM-III-R criteria (n = 126) from the epidemiologically based Roscommon Family Study, we systematically assessed 9 major symptoms, course, global outcome, Schedule for Negative Symptoms and the Levels of Functioning Scale. These clinical characteristics were related t the risk of mental disorders in first-degree relatives assessed by personal interview or hospital records (n = 354) utilizing both the "familial/sporadic" and the Cox proportional hazard models. Using either statistical method, no consistent and significant relationship was found between any of our measures of symptoms, course or outcome and the risk for schizophrenia or schizophrenia spectrum disorders in relatives. Similarly, no relationship was found between these clinical measures and the risk for affective illness, alcoholism or anxiety disorders. Our results are not consistent with previously articulated hypotheses that negative symptoms or poor outcome in schizophrenia reflect a high familial liability to illness. While familial factors contribute substantially to an individual's vulnerability to schizophrenia, our results suggest that once an individual is affected, these same factors do not strongly influence either the kinds of symptoms displayed or the course and outcome of the illness.