Background: The objective of this study was to determine the incidence of acute kidney injury (AKI) and its relation with mortality among hospitalized patients. Methods: Analysis of hospital discharge and laboratory data from an urban academic medical center over a 1-year period. We included hospitalized adult patients receiving two or more serum creatinine (sCr) measurements. We excluded prisoners, psychiatry, labor and delivery, and transferred patients, ‘bedded outpatients’ as well as individuals with a history of kidney transplant or chronic dialysis. We defined AKI as (a) an increase in sCr of ≥0.3 mg/dl; (b) an increase in sCr to ≥150% of baseline, or (c) the initiation of dialysis in a patient with no known history of prior dialysis. We identified factors associated with AKI as well as the relationships between AKI and in-hospital mortality. Results: Among the 19,249 hospitalizations included in the analysis, the incidence of AKI was 22.7%. Older persons, Blacks, and patients with reduced baseline kidney function were more likely to develop AKI (all p < 0.001). Among AKI cases, the most common primary admitting diagnosis groups were circulatory diseases (25.4%) and infection (16.4%). After adjustment for age, sex, race, admitting sCr concentration, and the severity of illness index, AKI was independently associated with in-hospital mortality (adjusted odds ratio 4.43, 95% confidence interval 3.68–5.35). Conclusions: AKI occurred in over 1 of 5 hospitalizations and was associated with a more than fourfold increased likelihood of death. These observations highlight the importance of AKI recognition as well as the association of AKI with mortality in hospitalized patients.