Plasma cell myelomas (PMs) have a poor prognosis. Cancer‐testis (CT) antigens are immunogenic proteins, representing potential targets for tumor vaccination strategies. The expression of the CT antigens GAGE, MAGE‐A4, MAGE‐C1/CT‐7, and NY‐ESO‐1 was investigated on paraffin‐embedded bone marrow biopsies from 219 PM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients. The frequency and prognostic impact of these CT antigens were compared with known morphological prognostic markers (i.e. Mib1 labeling index) and the presence of the translocations t(4;14)(p16.3; q32) and t(11;14)(q13;q32). We show that MAGE‐C1/CT‐7 is the most prevalent CT antigen, expressed in 57% of PMs in a high percentage of tumor cells. While MAGE‐C1/CT‐7 was absent in non‐malignant plasma cells, plasma cells of patients with MGUS did express MAGE‐C1/CT‐7, but no other CT antigens. MAGE‐C1/CT‐7 was more frequently expressed in PMs with an elevated proliferation rate (Mib1 >10%) compared to PMs with a low proliferation rate (Mib1 ≤10%, 71%versus 29%, P < 0.001) and correlated with overall survival, depending on its subcellular distribution. PMs with pure cytoplasmic MAGE‐C1/CT‐7 expression showed a better prognosis (48 months versus 33 months, P < 0.05) than PMs with combined nuclear‐cytoplasmic or nuclear expression only. Thus, expression of MAGE‐C1/CT‐7 in patients with monoclonal gammopathies represents a predictor of outcome and overt malignant transformation. (Cancer Sci 2008; 99: 720–725)