To assess sex-based differences in clinical outcomes following complex and high-risk but indicated percutaneous coronary intervention (CHiP). CHiP is increasingly common in contemporary percutaneous coronary intervention (PCI) practice. Data on sex differences in the type of CHiP procedures undertaken or their associated clinical outcomes are limited. Patients with stable coronary artery disease who underwent CHiP between January 1, 2006, and December 31, 2017, were included. All procedures were stratified by sex. Multivariate logistic regression analyses were performed to investigate the sex-specific adjusted odds ratios (aOR) of in-hospital outcomes. Out of 424,290 PCI procedures, 141,610 (33.37%) were CHiP procedures. Overall, 32,129 (23%) of CHiP were undertaken in females. Females were older than males (median: 74.8 vs. 69.1 years). Males had a higher prevalence of previous myocardial infarction (MI) (44.6% vs. 35.6%) and previous PCI (40% vs. 32.5%). The most common variable observed in female patients undergoing CHiP was age >80 (35.4%), followed by prior coronary artery bypass graft (CABG) (24.3%) and severe coronary calcification (22.6%). In contrast, the most common variable in male patients was prior CABG (36%), followed by chronic thrombus occlusion (CTO) PCI (34.4%) and severe coronary calcification (22%). Females had higher odds (aOR) for mortality (aOR: 1.78, 95% CI: [1.4, 2.2]), bleeding (aOR: 1.99, 95% CI: [1.72, 3.2]), and major adverse cardiovascular and cerebral events (aOR: 1.23, 95% CI: [1.09, 1.38]) compared to males. In this national analysis of CHiP procedures over 12 years, there were significant sex differences in the type of CHiP procedures undertaken, with females at increased odds for mortality and in-hospital adverse outcomes.