Multiple myeloma (MM) is an incurable malignancy of the plasma cells localized to the bone marrow. A rare population of MM cancer stem cells (MM-CSCs) has been shown to be responsible for maintaining the pull of residual disease and to contribute to myeloma relapse. The stem cells are found in a bone marrow niche in contact with the stromal cells that are responsible for maintaining the proliferative quiescence of the MM-CSC and regulate its self-renewal and differentiation decisions. Here we show that both MM and bone marrow stromal cells express N-cadherin, a cell-cell adhesion molecule shown to maintain a pool of leukemic stem cells. Inhibition of N-cadherin using a neutralizing antibody led to an increase in the MM cell proliferation. A decrease in MM cell adhesion to the bone marrow stroma was observed in the first 24 hours of co-culture followed by a 2.3-30-fold expansion of the adherent cells. Moreover, inhibition of N-cadherin led to a 4.8-9.6-fold expansion of the MM-CSC population. Surprisingly, addition of the N-cadherin antagonist peptide resulted in massive death of the non-adherent MM cells, while the viability of the adherent cells and MM-CSCs remained unaffected. Interestingly, the proliferative effects of N-cadherin inhibition were not mediated by the nuclear translocation of β-catenin. Taken together, our findings demonstrate the crucial role of N-cadherin in regulating MM cell proliferation and viability and open an interesting avenue of investigation to understand how structural modifications of N-cadherin can affect MM cell behavior. Our findings suggest that targeting N-cadherin may be a useful therapeutic strategy to treat MM in conjunction with an agent that has anti-MM-CSC activity.