The cellular mechanism(s) responsible for tumor-associated bone resorption in multiple myeloma remain uncertain. Both in vivo and in vitro evidence is presented for the direct resorption of bone by mouse plasmacytomas. Morphological examination of autopsy specimens from tumor-bearing mice revealed in vivo erosion of bony surfaces at sites of tumor cell-bone matrix apposition. No osteoclastic bone resorptive activity was evident. Using a 45Ca-labelled, devitalized bone explant assay system, mouse myeloma cells caused the release of isotope at levels from 200-300% above control values. Control cells such as normal spleen lymphocytes and liver cells did not resorb bone. Demonstration of the ability of myeloma cells to independently destroy bone is important to the understanding of the causes of and development of chemotherapeutic approaches to myelomatous bone resorption.