Background and Aims: Platelet P2Y12 is an important ADP receptor that is involved in agonists-induced platelet aggregation and is an important target for the development of anti-platelet aggregation drugs. The aim of the present study was to characterise the effects of uridine triphosphate (UTP) and its thio-(S)-analogues on ADP-induced platelet aggregation. Methods: The experiments were performed on platelet rich plasma freshly isolated from blood donated by healthy human volunteers. The investigation of molecular characteristics of these derivatives possibly associated with the inhibition of P2Y12 receptor was also carried out via molecular docking simulations. Results: UTP inhibited P2Y12 receptors and antagonised ADP-induced platelet aggregation in a conc.-dependent manner with an IC50 value of ~250 µM against ADP (10 µM). A 5-fold increase in the platelet inhibitory activity was observed by adding a thio (-S) group at position 2 (2S-UTP) of the nucleotide ring with an IC50 value of 30 µM. Interestingly, a 500-fold increase in anti-platelet aggregation activity was observed when a (-S) was introduced at position 4 of the nucleotide ring (4S-UTP) with an IC50 value of 7.5 µM. However, introducing an isobutyl group at the 4S- position reduced its activity by 2-fold with IC50 of 15 µM. A modeling study using FRED docking program was performed to dock these compounds into the ligand binding site of P2Y12 receptor. An excellent correlation was observed between the experimental findings and the docking results. Conclusion: The novel data demonstrate for the first time that thio (-S) analogues of UTP, particular 4S-UTP, are potent P2Y12 receptor antagonists and can be useful candidates for therapeutic intervention.