Immunohistochemistry (IHC) was performed on archived bone marrow (BM) with a phosphospecific anti-AKT antibody. IHC on 26 BM biopsies from patients with multiple myeloma (MM) demonstrated phospho-AKT staining of malignant plasma cells in a cell membrane–specific pattern, whereas nonmalignant hematopoietic cells did not stain. Preabsorption of the antibody with phosphorylated AKT peptide, but not nonphosphorylated peptide, abrogated staining. Frequency of plasma cell staining in BMs of patients with stage I or smoldering MM was significantly less than that of stage III MM marrows. Plasma cells in 10 patients with monoclonal gammopathy of undetermined significance were not stained by the antibody. To investigate the significance of AKT activation, 2 cell lines initiated from cultures of primary MM cells were also studied. Both demonstrated constitutive AKT activation. Interruption of AKT activation and activity, achieved by either exposure to wortmannin or by ectopic expression of a dominant negative AKT mutant, resulted in inhibition of MM cell growth in vitro. These results indicate that activation of the AKT kinase is a characteristic of MM cells and suggest that AKT activity is important for MM cell expansion.