Background: Inflammation plays a pivotal role in the pathogenesis of In-Stent Restenosis (ISR). High sensitivity C-reactive protein (hsCRP) is positively associated with major cardiovascular events. Aim: We aimed to investigate the hsCRP inflammatory response to Percutaneous Coronary Intervention (PCI) in Coronary Artery Disease (CAD) patients with coronary ISR vs. patients without ISR. Methods: This case-control study included 80 CAD patients previously treated with drug-eluting stent (DES) implantation. Patients had Coronary Angiography (CAG) because of chest pain or equivalent symptoms and were subdivided into 2 groups. Group A (n=40) included CAD patients with ISR. Group B (n=40) included age and gender-matched controls with CAD but without ISR. Serum hsCRP levels were obtained before PCI (baseline) and 8, 16, 24 h post-PCI. Results: At baseline (before intervention/CAG), the hsCRP level was increased in the ISR group compared with the No-ISR group (p=0.007). There were 36 (90%) patients in the ISR group who had a high hsCRP (>3 mg/L) compared with 25 (62.5%) patients in the No-ISR group. Also, there was a significant relationship between high hsCRP and the ISR. Patients with ISR had higher frequencies and percentages of elevated CRP than the noISR control group. This difference was maintained for all measurements, baseline, after 8, 16, and 24 h (p<0.05). Repeated measures analysis of variance ( ANOVA) in the ISR group revealed that mean hsCRP differed significantly between serial measurements (p<0.001). In contrast, in the control group, the mean hsCRP did not differ significantly between the serial measurements (p=0.65). Most of our patients (n=66, 82.5%) had 1-vessel CAD disease, and the left anterior descending (LAD) coronary artery was significantly affected in 46 patients (57.5%). Management of restenosis was accomplished mainly by stenting by DES in 29 patients (72.5%). Conclusion: Patients with ISR had substantially higher pre- and post-PCI hsCRP levels than the no-ISR controls. This difference was maintained up to 24h post-PCI. Conversely, the mean hsCRP did not significantly differ at the follow-up points for the controls without ISR.