We investigated the pathophysiology of fasting hypoglycemia associated with large tumors of mesenchymal origin. We studied two patients with symptomatic fasting hypoglycemia (plasma glucose, 1.92 and 2.03 mmol/L) and a large mesenchymal neoplasm. Before therapy, the plasma insulin-like growth factor II (IGF-II) level measured by RIA was elevated (1879 and 1084 micrograms/L; normal range, 358-854 micrograms/L), the serum GH response to hypoglycemia was impaired, and the plasma IGF-I level was low in both patients. After treatment of the tumor, all of these abnormalities resolved in both patients. Northern blot analysis of tumor RNA revealed extremely high levels of IGF-II mRNA (greater than 100-fold higher than those in normal adult liver). Tumor fragments released IGF-II into tissue culture medium (2.1 and 7.2 micrograms IGF-II/g tissue.24 h). These findings indicate that secretion of IGF-II into the circulation by the tumor was the likely source of the elevated plasma IGF-II levels. We suggest that the primary event in tumor-induced hypoglycemia is overproduction of IGF-II by the tumor, which gives rise to hypoglycemia by a dual mechanism: increased glucose utilization mediated by the insulin-like actions of IGF-II and inhibition of GH secretion.