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The appearance of acute non-lymphocytic leukemia (ANLL) in patients with other hematologic and non-hematologic malignancies is now a well recognized syndrome. These patients have an unusual form of leukemia with distinct clinical and morphological features. With improved therapy many cancer patients have experienced prolonged survival and cure. Some of these patients will develop ANLL as a consequence of their previous therapy, or for reasons associated with their primary tumor (host factors or common oncogenic virus). It is also possible that a fraction of these patients will develop the usual form of leukemia (de novo ANLL) that is unrelated to the underlying malignancy. Indeed, a statistical analysis assuming ANLL incidence rates to be unaffected by breast cancer or cancer therapy, predicted the occurrence of three new ANLL cases with a history of breast cancer in Wisconsin per year. Eleven patients with ANLL and a history of breast cancer were seen at the University Hospitals over a ten-year span (1969-1978). Clinical, morphological and cytogenetic features were examined and it was found that five of the eleven patients had features atypical for therapy related leukemia. Indeed, two of the patients had not received breast cancer therapy. The distinction between de novo and therapy related leukemia is important because remission and prolonged survival are more likely in the former and morbidity and mortality associated with therapy are more likely in the latter. We suggest that if features of de novo leukemia exist, despite previous therapy for underlying malignancy, intensive antileukemia therapy should be considered.