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Although an invasive strategy has predominately been studied in men with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), its role in low-risk women is unclear. We sought to examine gender differences in a real-world registry of patients with NSTE-ACS who underwent percutaneous coronary intervention (PCI). Patients with NSTE-ACS undergoing PCI at the Cleveland Clinic, Cleveland, Ohio from 2003 through 2007 (n = 1,874) were included. In-hospital and long-term mortalities were assessed. Cox proportional hazards models were constructed to study the influence of gender on mortality. Interactions with age and biomarker status were examined. Women were older and had a higher incidence of co-morbid conditions compared to men. They had a smaller reference vessel diameter compared to men. Despite these characteristics there was no overall difference in in-hospital (1.4% vs 1.6%) or long-term (14.6% vs 15.8%) mortality between men and women. However, there was evidence of a significant effect modification by age (p = 0.012) and troponin status (p = 0.0073) for long-term mortality such that women60 years of age, especially those who were troponin negative, had more than a twofold increase in long-term mortality compared to men (p = 0.007). In conclusion, although overall mortality rates are similar between men and women undergoing PCI for NSTE-ACS, women60 years old with negative biomarkers have a higher mortality than their men peers.