Drug-eluting stents (DES) reduce the incidence of in-stent restenosis (ISR) after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Whether the use of biomarkers might be of utility to identify patients who remain at risk for DES ISR after primary PCI has never been examined. A total of 26 biomarkers were measured at enrollment and 30 days and analyzed at a central core laboratory in 501 STEMI patients from the HORIZONS-AMI trial. All patients underwent primary PCI with the TAXUS paclitaxel-eluting stent (PES), were scheduled for routine angiographic follow-up at 13 months, and were followed for 3 years. Mean in-stent late-loss was 0.28 ± 0.57 mm, and target lesion revascularization (TLR) at 3 years occurred in 9.1 % of patients. Low levels of interleukin-6 (IL-6) and placental growth factor (PLGF) at admission were associated with both higher in-stent late loss and ischemia-driven TLR. Additionally, low admission levels of cardiotrophin-1 (CT-1) were associated with higher rates of ischemia-driven TLR. At 30-day follow-up lower values of IL-1ra (IL-1ra), matrix metalloproteinase 9 (MMP9), and myeloperoxidase (MPO), and a decline relative to admission in IL-1ra, monocyte chemotactic protein-1 (MCP-1), and MMP9 were associated with higher in-stent late loss. Low values of IL-6 at 30 days were also associated with ischemia-driven TLR. After multivariate adjustment, only MPO at 30 days and a decline of MCP-1 between admission and 30 days were associated with in-stent late loss, and only CT-1 was associated with TLR. MPO at 30 days and a decline of MCP-1 between admission and 30 days were independently associated with in-stent late loss, and CT-1 was associated with TLR. Additional studies to confirm and validate the utility of these biomarkers are warranted.