Objectives Despite progress in diagnosis and treatment, peptic ulcer disease (PUD) remains a common reason for hospitalization. The purpose of this study was to quantify the time trends of hospitalizations for PUD in the United States (U.S.) since 1993. Data and Methods The Healthcare Cost and Utilization Project Nationwide Inpatient Sample is a 20% stratified sample of all hospitalizations in the U.S. It was used to study hospitalizations with PUD as the principal diagnosis during 1993-2006, including details on ulcer site, complications, procedures, and mortality. Statistical methods included the chi-square test and multivariate logistic regression. Results The national estimate of hospitalizations for PUD decreased significantly from 222,601 in 1993 to 156,108 in 2006 (-29.9%), with a larger reduction in duodenal ulcers (95,552 in 1993 vs. 60,029 in 2006, -37.2%) than gastric ulcers (106,987 in 1993 vs. 86,064 in 2006, -19.6%). The inpatient mortality rate of PUD decreased from 3.8% to 2.7% during 1993-2006 (p<0.001). Hemorrhage remained the most common complication (71.6% in 1993; 73.3% in 2006) but perforation had the highest mortality (15.1% in 1993; 10.6% in 2006). In comparison to 1993, patients hospitalized for PUD in 2006 had more use of endoscopy to control bleeding (22.2% vs. 12.9%, p<0.001), similar use of oversewing of ulcer (7.4% vs. 7.6%), less use of gastrectomy (2.1% vs. 4.4%, p<0.001), and less use of vagotomy (1.7% vs. 5.7%, p<0.001). In multivariate logistic regressions, the determinants of mortality were similar in 1993 and 2006. Neither weekend admission nor low hospital PUD volume was associated with a higher mortality rate. Conclusions Hospitalizations for PUD have decreased in the U.S. from 1993 to 2006, suggesting a decrease in the prevalence and/or severity of ulcer complications over this recent time period. Over this time span, there has been a significant decrease in PUD mortality, a significant increase in the use of therapeutic endoscopy for bleeding ulcer, and a significant decrease in the use of definitive surgery (vagotomy and/or resection) for ulcer complications. Further research is necessary to determine if these trends are causally related.