Hypercalcemia is one of the metabolic complications associated with cancer. To assess the frequency of hypercalcemia in patients with squamous cell carcinoma (SCC), 242 patients who were evaluated as having SCC in the oral cavity between July 1995 and June 2001 were investigated. All patients were periodically monitored for their serum level of calcium (Ca). Hypercalcemia was defined as a serum Ca concentration higher than 11 mg/dl. By this definition, hypercalcemia was detected in 12 of the 242 patients (5.0%). All 12 patients were at an advanced stage of oral SCC. In these 12 patients, the serum level of parathyroid hormone-related protein (PTH-rP) was also significantly elevated. Therefore, we diagnosed these diseases as humoral hypercalcemia of malignancy (HHM). Moreover, we studied the efficacy of anti-hypercalcemic therapy on the quality of life (QOL). The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 was used for estimation of QOL. The patients with HHM who were administrated drugs such as bisphosphonate and calcitonin showed a reduction in their Ca and PTH-rP levels, and the six of ten EORTC QLQ-C30 subscales (emotional functioning, cognitive functioning, fatigue, dyspnoea, nausea/vomiting and appetite loss) were also improved after the anti-hypercalcemic therapy. However, these suppressive effects were temporary. The median survival time after the diagnosis of HHM was only 54.9+/-18.3 days (range 27-86 days). Therefore, HHM in SCC appears to be an ominous prognostic sign. Although anti-hypercalcemic therapy has a palliative role, the patients may be in less discomfort during the terminal stage of their illness.