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Background Gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and coronary artery disease (CAD) is associated with high morbidity and mortality. Methods The Nationwide Inpatient Sample (NIS) database from 1998 to 2006 was utilized to identify 1,216,759 PCIs performed for ACS and CAD. We sought to analyze temporal trends in the incidence and in-hospital outcomes of GIB associated with PCI along with its predictors. Results The overall incidence of GIB was 1.04% (95% confidence interval (CI), 1.02%–1.06%). The incidence of GIB decreased over the study period (p for trend <0.0001). The overall mortality in the GIB group was 6.0% (95% CI, 5.6%–6.4%). The adjusted odds ratio (OR) for in-hospital mortality and GIB was 4.70 (95% CI, 4.23–5.23; p<0.0001); this remained high and essentially unchanged over the study period. Independent predictors of GIB included rectum/anal cancer (OR, 4.64; 95% CI, 3.20–6.73; p<0.0001), stomach cancer (OR, 2.74; 95% CI, 1.62–4.66; p=0.0002), esophageal cancer (OR, 1.99; 95% CI, 1.08–3.69; p=0.0288), colon cancer (OR, 1.69; 95% CI, 1.43–2.02; p<0.0001), congestive heart failure (OR, 1.43; 95% CI, 1.35–1.52; p<0.0001), and acute myocardial infarction (OR, 1.23; 95% CI, 1.13–1.35; p<0.0001). Conclusions Although the incidence of GIB associated with PCI decreased from 1998–2006 in the face of aggressive therapies for ACS and CAD, the risk of GIB-associated death remained high. Underlying GI malignancy is a significant independent predictor of GIB associated with PCI; identifying these patients may reduce the rate of GIB.