Elevated levels of C-reactive protein (CRP) are present in many disease situations including malignancies and may contribute to the pathogenesis of cardiovascular disorders. This study was undertaken in a myeloma setting to determine whether CRP affects tumor cell growth and survival. We show that CRP enhanced myeloma cell proliferation under stressed conditions and protected myeloma cells from chemotherapy drug-induced apoptosis in vitro and in vivo. CRP binds activating Fcgamma receptors; activates PI3K/Akt, ERK, and NF-kappaB pathways; and inhibits caspase cascade activation induced by chemotherapy drugs. CRP also enhanced myeloma cell secretion of IL-6 and synergized with IL-6 to protect myeloma cells from chemotherapy drug-induced apoptosis. Thus, our results implicate CRP as a potential target for cancer treatment.