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Purpose: To determine the trends of infection sites and outcome of sepsis using a national population-based database., Materials and Methods: Using the Nationwide Inpatient Sample database of the US, adult sepsis hospitalizations and infection sites were identified using a validated approach that selects admissions with explicit ICD-9-CM codes for sepsis and diagnosis/procedure codes for acute organ dysfunctions. The primary outcome was the trend of incidence and in-hospital mortality of specific infection sites in sepsis patients. The secondary outcome was the impact of specific infection sites on in-hospital mortality., Results: During the 9-year period, we identified 7,860,687 admissions of adult sepsis. Genitourinary tract infection (36.7%), lower respiratory tract infection (36.6%), and systemic fungal infection (9.2%) were the leading three sites of infection in patients with sepsis. Intra-abdominal infection (30.7%), lower respiratory tract infection (27.7%), and biliary tract infection (25.5%) were associated with highest mortality rate. The incidences of all sites of infections were trending upward. Musculoskeletal infection (annual increase: 34.2%) and skin and skin structure infection (annual increase: 23.0%) had the steepest increase. Mortality from all sites of infection has decreased significantly (trend p<0.001). Skin and skin structure infection had the fastest declining rate (annual decrease: 5.5%) followed by primary bacteremia (annual decrease: 5.3%) and catheter related bloodstream infection (annual decrease: 4.8%)., Conclusions: The anatomic site of infection does have a differential impact on the mortality of septic patients. Intra-abdominal infection, lower respiratory tract infection, and biliary tract infection are associated with higher mortality in septic patients., Competing Interests: The authors have declared that no competing interests exist.