Statins are powerful agents for lowering plasma cholesterol levels, which act by inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase. Evidence suggests that some of the beneficial effects may depend on their anti-inflammatory properties, due to their ability to suppress the synthesis of isoprenoids. The present study analyzes the effects of short-term simvastatin exposure on monocyte migration, cell adhesion, and endothelial cytoskeleton. We demonstrate that simvastatin completely inhibited the migration of THP-1 monocytic cells after 24 h of incubation, being prevented by coincubation with mevalonate (MVA) and geranylgeranylpyrophosphate (GGPP), but not by farnesylpyrophosphate (FPP). Simvastatin decreased chemotaxis to 70% after one hour of incubation; surprisingly neither MVA, GGPP nor FPP were able to restore the effects of the drug. Simvastatin also significantly reduced the adhesion of monocytes to interleukin-1beta (IL-1beta)-activated endothelium to 80% after preincubation for 24 h. This effect was completely reversed by coincubation with MVA and GGPP, and partially with FPP. Unexpectedly, simvastatin increased adhesion molecules expression VCAM-1 and ICAM-1 on cytokine-stimulated endothelial cells. Examination of the actin cytoskeleton on IL-1beta-activated endothelial cells showed that both 4 and 24 h of incubation with simvastatin produced a complete disappearance of F-actin, being completely restored by MVA and partially by GGPP and FPP after 24 h of coincubation. We suggest that cytoskeleton disorganization in endothelial cells is important for inhibiting monocyte adhesion, altering the adhesion molecules function. Taken together, these results strongly support the beneficial anti-inflammatory properties of statins, contributing to the overall clinical effects.