Despite the valuable role of intravascular ultrasound (IVUS) guidance in percutaneous coronary interventions (PCIs), its impact on clinical outcomes remains debatable. The aim of the present study was to compare the outcomes of PCIs guided by IVUS versus angiography in the contemporary era on inhospital outcomes in an unrestricted large, nationwide patient population. Data were obtained from the Nationwide Inpatient Sample from 2008 to 2011. Hierarchical mixed-effects logistic regression models were used for categorical dependent variables like inhospital mortality, and hierarchical mixed-effects linear regression models were used for continuous dependent variables like length of hospital stay and cost of hospitalization. A total of 401,571 PCIs were identified, of which 377,096 were angiography guided and 24,475 (weighted n = 119,102) used IVUS. In a multivariate model, significant predictors of higher mortality were increasing age, female gender, higher baseline co-morbidity burden, presence of acute myocardial infarction, shock, weekend and emergent admission, or occurrence of any complication during hospitalization. Significant predictors of reduced mortality were the use of IVUS guidance (odds ratio 0.65, 95% confidence interval 0.52 to 0.83; p <0.001) for PCI and higher hospital volumes (third and fourth quartiles). The use of IVUS was also associated with reduced inhospital mortality in subgroup of patients with acute myocardial infarction and/or shock and those with a higher co-morbidity burden (Charlson's co-morbidity index ≥2). In one of the largest studies on IVUS-guided PCIs in the drug-eluting stent era, we demonstrate that IVUS guidance is associated with reduced inhospital mortality, similar length of hospital stay, and increased cost of care and vascular complications compared with conventional angiography-guided PCIs.