After percutaneous coronary intervention (PCI), it is unknown whether retained lipid content in the stented segment increases the risk of target lesion failure (TLF). This study evaluated the association between retained lipid content in the stented segment detected by post-PCI intracoronary near-infrared spectroscopy and TLF. Approach and Results: After the performance of PCI, post-PCI near-infrared spectroscopy-intravascular ultrasound images were acquired and analyzed by an independent core laboratory for retained lipid content in the stented segment, quantified by the maximum lipid core burden index in 4 mm (maxLCBI4mm). The primary outcome was TLF during follow-up, defined as a composite of cardiovascular death, target vessel myocardial infarction, and clinically driven target lesion revascularization. Among 202 patients with 209 target lesions treated by PCI and followed for 3.5±1.4 years, baseline post-PCI near-infrared spectroscopy-intravascular ultrasound images revealed a significantly greater maxLCBI4mm in stented lesions with (297 [211, 401]) versus without (119 [9, 258]) TLF during follow-up (P=0.006). By multivariate logistic regression, maxLCBI4mm in the stented segment was independently associated with subsequent TLF (odds ratio, 1.6 [95% CI, 1.2-2.1] for every 100-unit increase, P=0.004). By receiver-operating characteristic analysis, the optimal residual maxLCBI4mm threshold in the stented segment for subsequent TLF was 200. Stented lesions with a residual maxLCBI4mm >200 had significantly greater TLF during follow-up than stented lesions with a maxLCBI4mm ≤200 (15.0% versus 3.1%, P=0.002). Retained lipid content detected by near-infrared spectroscopy in the stented segment after PCI was associated with an increased risk of subsequent TLF.