OBJECTIVE Some children who survive a childhood malignancy have diminished bone mineral density (BMD). The purpose of this study is to assess when, and perhaps why, this problem develops. METHODS BMD was longitudinally monitored in 37 children for a minimum of 1 year (mean, 23.4 months; range, 12 to 41 months) during and, in some cases, after chemotherapy. Evaluations included serum analyses (vitamin D, calcium, and alkaline phosphatase), assessment of calcium intake, and measures of growth and nutrition (height, weight, and skinfolds). RESULTS BMD was already diminished at the start of treatment in some patients; 6 of 13 patients (46%) had a BMD z score in the hip or spine of < -1.0. However, only 1 patient (8%) was < -2.0. Most patients did not have a significant drop in BMD z scores during chemotherapy, but one in four did decrease at least 0.5 standard deviations. Age greater than 10 years, a drop in height z score, and treatment with cranial irradiation correlated with a drop in BMD z scores during treatment. In the year immediately after completion of chemotherapy, no consistent "catch-up" was observed in BMD z scores. CONCLUSIONS In some patients, BMD z scores are diminished at the time of diagnosis and a drop may occur during treatment in others. Multiple factors related to the disease process and treatment likely contribute to these observations. Cranial irradiation, perhaps by impacting on growth hormone homeostasis, is one such factor. Fortunately, most survivors of a childhood malignancy will not have large deficits in BMD later in life.