Multiple myeloma (MM) is an incurable disease accompanied by low plasma levels of low-density lipoprotein cholesterol (LDL-c). The significance of altered cholesterol metabolism in the pathophysiology of MM remains elusive. Although it has been hypothesized that myeloma cells depend on exogenous cholesterol for its survival, the role of LDL-c on myeloma cells has not been elucidated. To evaluate the impact of exogenous LDL-c on cell viability, three human myeloma cell lines (RPMI-8226, NCI-H929, and U-266B1) were grown in the presence or absence of lipoproteins. Cell viability was markedly reduced in the absence of lipoproteins in sera. However, exogenous LDL-c improved cell viability. We showed that reduced cell viability was associated with increased levels of cleaved caspase-3, whereas proliferation rate remained unchanged. Interestingly, exogenous LDL-c counteracted apoptosis in human myeloma cell lines and primary cultures of human myeloma cells. Thus, our results demonstrated that LDL-c is an important anti-apoptotic factor for myeloma cells and begin to explain the hypocholesterolemia observed in patients with MM.