Aim To elucidate the intracellular signaling pathways for β-very low density lipoprotein (VLDL) -induced VLDLR transcription and their effects on lipid accumulation in macrophages. Methods Phosphorylated extracelcular signal regucated kinase (ERK1/2) protein was detected with Western blot. mRNA level of VLDL receptor was assayed by RT-PCR.Results We found that β-VLDL induced an increase in ERK1/2 activity in a protein kinase C (PKC)-dependent manner in murine RAW264.7 macrophages. Studies using different protein kinases inhibitors or activators showed that the effect of β-VLDL induced VLDL receptor transcription, which was monitored by RT-PCR analysis of VLDL receptor mRNA, was not affected by the inhibitor of P38 kinase and cAMP analog, but extremely abolished by pretreating cells with an inhibitor of ERK and an inhibitor of PKC. Studies on effects of PD98059 (the inhibitor of ERK) on β-VLDL-induced cellular lipid accumulation, which was assessed by cholesterol and triglycerid assay kit showed that ERK inhibitor decreased cellular cholestorol and triglycerid increase exposed to β-VLDL in a dose-dependent manner. Conclusions These results demonstrated that the PKC-ERK1/2 cascade was the essential signaling pathway by which β-VLDL activated VLDL receptor mRNA expression and inhibition of the ERK1/2 signaling cascade resulted in suppression of the cellular lipid accumulation induced by β-VLDL in macrophages.