Vascular occlusive disease is a leading cause of death and disability worldwide. The development over the last decades of vascular interventions has represented a huge therapeutical improvement. A limitation of these procedures is restenosis of the target vessel because of the arterial repair mechanisms. Mechanical or chemical injury promotes dedifferentiation of the vascular smooth muscle cells (VSMCs) through a process known as phenotypic modulation. VSMCs develop a proliferative, migratory and secretory phenotype directed to intimal hyperplasia (IH). Restenosis after vascular surgery is accelerated in pathological vessels, as the underlying disease will determine prognosis. Among these, metabolic syndrome and type II diabetes mellitus (DM), represent the dark side of restenosis, showing increased IH and worse outcomes. We have recently found that phenotypic modulation associates with an increased functional expression of the voltage-dependent potassium channel Kv1.3, and that selective blockade of this channel decreases human VSMC proliferation in vitro and neointima formation in vivo. Here, we compare the effect of PAP-1 (a Kv1.3 selective blocker) with everolimus (the gold standard in clinical practice) on the remodeling of human mammary artery (hMA) in organ culture and on proliferation and migration of VSMC in culture. These studies were carried out in non-diabetic (NDM) and diabetic patients (DM). hMAs were obtained from donors after approval by the Hospital Ethics Committee according to the standards of the Helsinki Declaration. IH in organ culture was induced after two weeks incubation using fetal bovine serum. Intimal/media ratio (I/M) shows that IH is increased in DM vessels compared to NDM. PAP-1 treatment inhibited IH in both groups, being more effective in DM vessels (I/M ratio of 0.46±0.13 in DM versus 0.73±0.04 in NDM, p<0.05, t-test). However, everolimus was only effective in DM vessels. Surprisingly, no inhibitory effect was observed when both drugs were applied together. Additionally, PAP-1 inhibited proliferation and decreased the amount of elastin in organ culture. In primary VSMCs cultures from hMAs, PAP-1 and everolimus inhibited proliferation to a similar extent, and their effects were additive only in NDM VSMCs. Migration assays showed that PAP-1 had an inhibitory effect in NDM and DM cultures but everolimus only inhibited DM samples. Altogether, our data highlight Kv1.3 channels as a promising target against IH in human vessels and suggest that diabetes induces long-term changes in the IH signaling pathways that could be relevant when possible therapeutical approaches are considered. Funding. Supported by grants BFU2016-75360-R (MINECO), VA114P17 (JCyL) and by a University of Valladolid fellowship to MAM.