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 immuno-histochemistry, 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 0s (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.