Intracoronary imaging has become an important tool in the treatment of complex lesions with percutaneous coronary intervention (PCI). This retrospective cohort study identified 1,118,475 patients with PCI from the Nationwide Readmissions Database from 2017 to 2019. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) were identified with appropriate International Classification of Diseases, Tenth Revision codes. The primary outcome was major adverse cardiac events. The secondary outcomes include net adverse clinical events (NACEs), all-cause mortality, myocardial infarction (MI) readmission, admission for stroke, and emergency revascularization. The multivariate Cox proportional hazard regression was used to adjust for demographic and co-morbid confounders. Of 1,118,475 PCIs, 86,140 (7.7%) used IVUS guidance and 5,617 (0.5%) used OCT guidance. The median follow-up time was 184 days. The primary outcome of major adverse cardiac events was significantly lower for the IVUS (6.5% vs 7.6%; hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.91, p <0.001) and OCT (4.4% vs 7.6%; HR 0.69, 95% CI 0.61 to 0.79, p <0.001) groups. IVUS was associated with significantly lower rates of NACEs (8.4% vs 9.4%; HR 0.92, 95% CI 0.89 to 0.94, p <0.001), all-cause mortality (3.5% vs 4.3%; HR 0.85, 95% CI 0.82 to 0.88, p <0.001), readmission for MI (2.7% vs 3.0%; HR 0.95, 95% CI 0.91 to 0.99, p = 0.012), and admission for stroke (0.5% vs 0.6%; HR 0.86, 95% CI 0.78 to 0.95, p = 0.002). OCT was associated with significantly lower rates of NACEs (6.6% vs 9.4%; HR 0.81, 95% CI 0.73 to 0.89, p <0.001) and all-cause mortality (1.8% vs 4.3%; HR 0.51, 95% CI 0.42 to 0.63, p <0.001). Emergency revascularization was not significantly different with IVUS guidance. Readmission for MI, stroke, and emergency revascularization were not significantly different with OCT guidance. A subgroup analysis of patients with ST-elevation MI and non-ST-elevation MI showed similar results. In conclusion, the use of IVUS and OCT guidance with PCI were associated with significantly lower rates of morbidity and mortality in real-world practice.