Postprandial triacylglycerol-rich lipoproteins (TRL) have been implicated in the pathophysiology of atherosclerosis, but the intracellular processes by which TRL could affect vascular function are still unknown. Incubation of TRL obtained at 2 h postprandial period with vascular smooth muscle cells (VSMC) produced a tyrosine phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) that belong to the mitogen-activated protein kinase (MAPK) family. The activation of ERK1 and ERK2 had a maximum at 15 min, returned to baseline by 60 min, and was partially depleted after incubation of cells with a MAPKK inhibitor (PD 098059). In addition, postprandial TRL did competent VSMC for DNA replication through a MAPK pathway. These effects were dependent of the lipid composition of TRL. Our observations suggest that postprandial TRL can trigger activation of the MAPK pathway and induce a mitogenic response in VSMC in a lipid-dependent fashion.