Background: Among the chemokines related to CXC and CC receptor groups and released from platelets, leukocytes and endothelial cells, SDF-1, TARC and MDC have been found to be platelet agonists. Platelets do not contain SDF-1α. In contrast, RANTES is constitutively present in platelet α-granules and released upon platelet activation. Objectives: To study a possible role of RANTES as a modulator of SDF-1α effect on platelets, in relation to CXCR4 and various CC receptors. Methods: CXCR-4 (CXCL12) receptor expression and platelet activation were evaluated by flow cytometry, platelet deposition was studied by cone and plate(let) analyzer, and platelet aggregation by turbidometric aggregometry. Results: Flow cytometry studies revealed similar expression of CXCR-4, the specific receptor of SDF-1α on intact, inactivated, and activated platelets. Preincubation of platelets with RANTES affected neither CXCR-4 expression, nor SDF-1α binding to the platelet membrane. In the presence of fibrinogen, SDF-1α activated gel-filtered platelets. RANTES did not activate platelets, but substantially (by 70%) inhibited SDF-1α-induced fibrinogen binding. Similarly, RANTES abrogated the promoting effect of SDF-1α on whole blood platelet adhesion to endothelial cell monolayer under venous flow conditions. In platelet-rich plasma, RANTES moderately inhibited SDF-1α-induced platelet aggregation, while it did not affect aggregation induced by thrombin-receptor activation peptide, adenosine diphosphate, or phorbol 12-myristate 13-acetate. A synergistic inhibitory effect of RANTES and prostaglandin E1 used at subthreshold concentrations, on SDF-1α-induced aggregation and SDF-1α-induced fibrinogen binding to platelets was observed, which may suggest involvement of RANTES in a cAMP-dependent signal transduction pathway. Conclusions: RANTES non-competitively inhibits activation of platelets by SDF-1α, and thus may play a regulatory role in platelet response to inflammation.