The adipokine leptin elicits changes in the expression of the activation markers CD40 and CD69 in PBMCs and DCs, yet its effect on pattern recognition receptors remains to be elucidated. Serum leptin concentrations are elevated in obesity and T2DM, which are both diseases associated with a pro-inflammatory state. We therefore investigated a possible role for leptin in monocyte TLR and CD14 expression. Leptin increased TLR2 cell surface and mRNA expression in THP-1 and primary human monocytes. In contrast, leptin had no effect on monocyte TLR4 expression in either THP-1 or primary monocytes. Both CD14 cell surface and mRNA expression were increased after leptin stimulation in THP-1 monocytes. However, no change in cell surface CD14 expression was observed after leptin treatment in primary human monocytes. Leptin also up-regulated the expression of PU.a and EGR2, transcription factors involved in myeloid cell differentiation. Additionally, leptin potentiated both E. coli and P. gingivalis LPS-induced TNF-α secretion in THP-1 monocytes. In conclusion, we show that leptin and LPS differentially influence monocyte phenotype and demonstrate for the first time a regulatory effect of leptin on the monocyte expression of TLR2. Leptin-stimulated TLR2 expression may potentiate innate immunity and inflammation in conditions of hyperleptinemia such as obesity and T2DM.