Thalidomide and its analogs have been extensively studied in patients with multiple myeloma. We present the case of a 58-year-old female patient with immunoglobulin GA-kappa multiple myeloma who was receiving thalidomide after failing an autologous transplant. She presented with profound asthenia and several space-occupying hepatic lesions, one of which was shown by a CT-guided percutaneous biopsy to be plasmacytoma. The patient then received bortezomib and had a transient response. Because thalidomide may also increase the expression of cytoadhesion molecules in myeloma cells and in the bone marrow microenvironment, it is possible that some patients with multiple myeloma who relapse on thalidomide may present with extramedullary plasmacytomas, as seen in this case. Therefore, whenever symptoms arise in patients with multiple myeloma who are receiving thalidomide, extramedullary plasmacytomas should be considered.