Leptin, a peptide secreted from adipose tissue, along with other tissues, to act on the hypothalamic leptin receptors to decrease food intake and increase energy expenditure. Obesity is increased production of the 16-kDa peptide leptin, which is also elevated in cardiovascular disease such as heart failure. And recently, leptin is known to directly induce hypertrophy in rat neonatal cardiomyocytes. The hypertrophy of vascular smooth muscle cell (SMC) is critical in vascular remodeling associated with hypertension, atherosclerosis, and restenosis. We therefore studied the effect of leptin as a potential hypertrophic factor in rat vascular smooth muscle cells. In the present study, we showed that leptin significantly increased [3H]leucine incorporation and total protein/DNA ratio. The maximal hypertrophic effect was observed at 100 ng/mL (6.1 nmol/L) of leptin, and half maximal effect was 10 ng/mL (0.61 nmol/L). Using immunoblot analysis, leptin stimulated the phosphorylation of p38 MAP kinase (p38 MAP kinase) and signal transducers and activators of transcription 3 (STAT3) after 5 min of leptin treatment. In this time, hypertrophy was completely inhibited by the p38 MAP kinase inhibitor SB203580 but not by the JAK2 inhibitor AG490. These results demonstrate that leptin stimulates hypertrophy directly via p38 MAP kinase in rat vascular smooth muscle cells.