Prior studies of myeloma treated with conventional chemotherapy or autologous stem cell transplantation have shown immunohistochemistry for cyclin D1, fibroblast growth factor receptor 3, and p53 to be prognostically significant. The clinical significance of these phenotypic abnormalities in thalidomide-based regimens is currently unknown. We examined the clinical significance of immunohistochemistry for cyclin D1, fibroblast growth factor receptor 3, p53, and cyclin D3 in 94 patients treated with pegylated doxorubicin, vincristine, dexamethasone, and thalidomide, including 49 newly diagnosed and 45 relapsed/refractory patients. The incidence of positivity for cyclin D1, fibroblast growth factor receptor 3, p53, and cyclin D3 was similar in newly diagnosed versus relapsed/refractory groups (37%, 8%, 4%, and 2% versus 42%, 7%, 11%, and 2%, respectively). In contrast to prior studies of other therapeutic regimens, cyclin D1 negativity or fibroblast growth factor receptor 3 positivity did not convey an adverse progression-free or overall survival. p53 positivity, although uncommon, was associated with shorter progression-free and overall survival in newly diagnosed cases. The findings suggest that a thalidomide-based regimen may overcome the poor prognosis associated with a cyclin D1-negative or fibroblast growth factor receptor 3-positive phenotype.