Intravascular ultrasound (IVUS) guided percutaneous coronary intervention (PCI) is indicated in complex interventions. There is a paucity of evidence for outcomes with large studies on using IVUS during PCI in non–ST-elevation myocardial infarction (NSTEMI). Our objective was to compare the in-hospital outcome of IVUS-guided with that of nonguided PCI among NSTEMI hospitalizations. The National Inpatient Sample (2016 to 2019) was queried to identify all hospitalizations with a principal diagnosis of NSTEMI. In our study, we compared outcomes of PCI with and without IVUS guidance using a multivariate logistic regression model after propensity score matching, with the primary outcome being in-hospital mortality. A total of 671,280 NSTEMI-related hospitalizations were identified, of whom 48,285 (7.2%) underwent IVUS-guided PCI compared with 622,995 (92.8%) who underwent non-IVUS PCI. After adjusted analysis on matched pairs, we found that IVUS-guided PCI had a lower risk of in-hospital mortality than that of non-IVUS PCI (adjusted odds ratio [aOR] 0.736, confidence interval (CI) 0.578 to 0.937, p = 0.013). However, there was a higher use of mechanical circulatory support in the IVUS-guided PCI (aOR 2.138, CI 1.84 to 2.47, p <0.001) than in non-IVUS PCI. The odds of cardiogenic shock (aOR 1.11, CI 0.93 to 1.32, p = 0.233) and procedural complications (aOR 0.794, CI 0.549 to 1.14, p = 0.22) were similar between the cohorts. Hence, we conclude that patients with NSTEMIs who underwent IVUS-guided PCI had less risk of in-hospital mortality and a greater requirement of mechanical circulatory support than did those who underwent non-IVUS PCI, with no difference in procedural complications. Large prospective trials are essential to validate these findings.