We assessed the effect of leptin on human monocytes. Monocytes were isolated from 16 healthy obese and 10 lean healthy participants. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Obese participants were subdivided into 2 subgroups, insulin sensitive (IS) and insulin resistant (IR). Monocyte properties (attachment to laminin 1, migration through laminin 1, surface expression of CD36, oxidized low-density lipoprotein [oxLDL] phagocytosis) were assessed pre- and poststimulation in vitro with leptin. Experiments were repeated after incubation with rosiglitazone and a Na(+)/H(+) exchanger-1 inhibitor (cariporide). We found a significant correlation between insulin resistance and monocyte attachment to laminin and oxLDL phagocytosis. Leptin increased the atherosclerosis-related properties of monocytes in all groups, apart from surface expression of CD36 in IS obese participants. Incubation with rosiglitazone or cariporide attenuated the observed effects. Leptin induces monocyte dysfunction which may be atherogenic. Correlation with insulin resistance suggests that atherosclerosis might be accelerated before the onset of diabetes.