High levels of B-type natriuretic peptide in cancer patients are poorly studied. Previously published data suggest that they are not related to fluid overload and are encountered mostly in solid cancers. The authors investigated the distribution of amino terminal pro-brain natriuretic peptide (NT-proBNP) between hematologic and solid organ malignancies and the relationship of NT-proBNP with volume status in oncologic patients. A total of 145 consecutive patients with at least one occurrence of NT-proBNP exceeding the upper normal range 10-fold were identified. The authors retrospectively reviewed their records including clinical, laboratory, and radiological data and echocardiograms. More than 70% of patients had hematologic malignancies. Patients with NT-proBNP >50,000 pg/mL had only hematologic malignancies, primarily multiple myeloma. There was no association between M-spike proteins and NT-proBNP. About 80% of patients had signs of fluid overload. The magnitude of NT-proBNP elevation was similar between those with and without heart failure or volume overload, as well as with solid cancers vs hematologic malignancies. Contrary to prior reports, it was found that very high NT-proBNP in cancer patients is usually encountered in the context of fluid overload and most often in hematologic malignancies.