The major vault protein (MVP), a ribonucleoprotein complex which mediates the transport of xenobiotic toxins, has been implicated in multidrug resistance (MDR) not mediated by p-glycoprotein (P-gp) or multidrug resistance related protein (MRP). We evaluated, via immunohistochemistry, the presence of MVP in plasma cells of myeloma patients. Among 73 patients registered with the Southwest Oncology Group (SWOG), 52 patients (74%) were positive for MVP. The presence of MVP and P-gp were significantly associated (p < 0.01). A univariate analysis of response versus MVP positivity showed borderline statistical significance (p = 0.043) with no association with OS or PFS. In particular, MVP positivity at first biopsy was associated with non-responsiveness to therapy (7/7 patients, 100%). MRP was not present in any of 23 samples tested. An increased proliferative rate (Ki-67 > 5%) was significantly associated with shorter OS (log rank p-value = 0.0002). The collective work indicates that MVP protein is common and abundant in myeloma with potential relevance to therapeutic response.