In-stent restenosis (ISR) remains the primary concern after a percutaneous coronary intervention (PCI) and is considered to be associated with worse clinical outcomes. However, comparative data on ISR and de novo lesions are rare. Therefore, we aimed to compare PCI-related clinical outcomes between patients with de novo lesions and those with ISR lesions. We undertook a retrospective analysis of patients who had undergone a PCI between 2013 and 2020. The incidences of major adverse cardiac and cerebrovascular events (MACCE) and all-cause death over a 2-year follow-up period were evaluated. In total, 1538 patients were enrolled and divided into two groups: a de novo lesions group (n = 1258, 81.8%) and an ISR lesions group (n = 280, 18.2%). Patients in the ISR lesions group were significantly older, with a higher prevalence of hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease than those in the de novo lesions group. Kaplan-Meier curves showed no significant between-group differences in the incidence of MACCE (log-rank, p = 0.93) and all-cause death (p = 0.09). After adjustment for other covariates, PCIs for ISR lesions were not found to be significantly associated with MACCE (hazard ratio [HR], 1.10; 95% confidential interval [CI] 0.49-2.49; p = 0.81) and all-cause death (HR, 0.58; 95% CI 0.26-1.31; p = 0.19). PCIs for ISR lesions were not associated with worse clinical outcomes compared with PCIs for de novo lesions.