The authors report a case of multiple myeloma with increased accumulation of Tc-99m hexamethylpropylene amine oxime (HMPAO) on brain SPECT. Tc-99m HMPAO is a lipophilic compound that freely passes through the intact blood-brain barrier and cell membrane and is rapidly converted to a hydrophilic form by glutathione and then retained in the neuron for several hours. In general, Tc-99m HMPAO shows decreased accumulation in brain tumors. However, some reports of increased accumulation in brain tumors, such as meningioma, glioblastoma multiforme, high-grade astrocytoma, pituitary adenoma, and multiple myeloma, have been published. The Tc-99m HMPAO uptake in these tumors has been attributed to tumor blood flow or glutathione contents within the tumor. With regard to uptake to Tc-99m HMPAO in multiple myeloma, the tumor size is considered to be an additional factor.