To provide further understanding of humoral hypercalcemia in Hodgkin's disease (HD) the authors describe the clinical features and laboratory investigation of three patients recently treated at Massachusetts General Hospital. All were middle-aged men who presented with symptomatic hypercalcemia which led to a diagnosis of bulky intraabdominal HD. None had evidence of bone involvement or hyperparathyroidism. In the two cases tested 1,25(OH)2D3 was elevated at the time of diagnosis. These characteristics are remarkably similar to those of ten patients with HD and probable humoral hypercalcemia described in the literature. The diagnosis of HD was supported in Cases 1 and 3 by genomic blot analysis which showed no evidence of T-cell or B-cell tumor origin. In an in vitro assay, primary tumor medium from Case 1 stimulated dose-dependent bone resorption which was not entirely ascribable to 1,25(OH)2D3. The authors conclude that humoral hypercalcemia in HD predominantly affects males of middle age, that intraabdominal bulky disease is common, and that hypercalcemia appears to be mediated by tumor related production of 1,25(OH)2D3 in concert with a second factor.