Previous observations in the bare metal stent (BMS) era have demonstrated an association between a high preprocedural C-reactive protein (CRP) level and an increased incidence of death or myocardial infarction after percutaneous coronary intervention (PCI). We hypothesized that PCI with sirolimus-eluting stents (SESs) would result in a smaller increase in CRP compared with BMSs and that a high CRP level before PCI would be associated with a higher incidence of death or myocardial infarction at 12 months, regardless of the type of stent implanted. We analyzed patients who underwent PCI with stenting at the Cleveland Clinic Foundation. Patients who received BMSs and SESs were analyzed separately by categorizing them into low and high CRP groups based on whether their CRP level before PCI was above or below the median for each group. The increase in CRP that occurred with PCI was termed ΔCRP. In total, 652 patients were included in the analysis. Median ΔCRP was smaller in the SES group than in the BMS group (1.5 vs 0.7 mg/L, p = 0.009). In the BMS group, patients with a CRP level above the median before PCI had a higher incidence of 12-month death or myocardial infarction compared with patients with a CRP level below the median (11.3% vs 1.6%, p = 0.002). The same relation was present in the SES group, i.e., patients with a higher CRP level had a higher incidence of 12-month death or myocardial infarction compared with patients with a low CRP level (6.3% vs 1.0%, p = 0.005) and a higher 12-month mortality (5.2% vs 0%, p = 0.001). Multivariate logistic regression analysis demonstrated that the CRP level above the median before PCI was associated with a higher 12-month incidence of death or myocardial infarction, independent of the type of stent used, or ΔCRP. In conclusion, PCI in the SES era causes a smaller increase in CRP compared with the BMS era. A high CRP level before PCI is independently associated with a higher risk of long-term death or myocardial infarction. This finding was present in the BMS and SES groups and highlights the need for aggressive risk-factor modification after PCI.