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We have previously shown that overall cost of hospitalization for emergency general surgery (EGS) diseases is more than $28 billion annually and rising. The purposes of this study were to estimate the costs associated with specific EGS diseases and to identify factors associated with high-cost hospitalizations.The American Association for the Surgery of Trauma definition was used to identify hospitalizations of adult EGS patients in the 2010 National Inpatient Sample data. Cost of each hospitalization was obtained using cost-to-charge ratio in National Inpatient Sample. Regression analysis was used to estimate the cost for each EGS disease adjusted for patient and hospital characteristics. Hospitalizations with cost exceeding 75th percentile for each EGS disease were compared with lower-cost hospitalizations to identify factors associated with high cost.Thirty-one EGS diseases resulted in 2,602,074 hospitalizations nationwide in 2010 at an average adjusted cost of $10,110 (95% confidence interval, $10,086–$10,134) per hospitalization. Of these, only nine diseases constituted 80% of the total volume and 74% of the total cost. Empyema chest, colorectal cancer, and small intestine cancer were the most expensive EGS diseases with adjusted mean cost per hospitalization exceeding $20,000, while breast infection, abdominal pain, and soft tissue infection were the least expensive, with mean adjusted costs of less than $7,000 per hospitalization. The most important factors associated with high-cost hospitalizations were the number and type of procedures performed (76.2% of variance), but a region in Western United States (11.3%), Medicare and Medicaid payors (2.6%), and hospital ownership by public or not-for-profit entities (5.6%) were also associated with high-cost hospitalizations.A small number of diseases constitute a vast majority of EGS hospitalizations and their cost. Attempts at reducing the cost of EGS hospitalization will require controlling the cost of procedures.Economic analysis, level IV.