The success of percutaneous coronary intervention (PCI) procedures is limited by in-stent restenosis (ISR). The use of drug-eluting stents (DES) decreased the incidence of ISR; however, ISR continues to affect a percentage of patients with ischemic cardiac events. Therefore, there is room for improvement considering not only the effectiveness of DES but also the adjunct pharmacological interventions for patients after PCI. Interleukin 6 (IL-6) can stimulate the growth of vascular smooth muscle cells (SMCs) in a platelet-derived growth factor (PDGF)-dependent manner and that antibodies against the IL-6 receptor reduced intimal hyperplasia in mice. In this study, our aim is to develop an in vitro study, based on co-cultures of endothelial cells (EC) and SMCs in the presence of platelets and stents, to analyze the cytokine responses (IL-6 and other inflammation markers) associated with ISR, in the quest for new therapeutic targets. Overall, in the presence of platelet-rich plasma (PRP), there was an increase in the production of reactive oxygen species in the groups that received the stents, probably because platelets potentiate stent-associated oxidative stress. Moreover, the analysis of the expression of inflammatory markers showed a difference in the expression of IL-6 only in the groups that received stents, which further increased in the presence of platelets. Altogether, our findings suggest that the down regulation of IL-6 expression using pharmacologic inhibitors is a possible new therapeutic strategy in the context of ISR.