A history of renal insufficiency or increased creatinine level on admission is associated with poor outcomes in patients with acute coronary syndrome (ACS). This study sought to determine whether in-hospital worsening of renal function, either transient or sustained, is an independent risk factor for 6-month mortality in patients admitted with ACS. A total of 1,417 patients admitted with ACS from June 2000 to May 2003 were reviewed. Patients were classified into 3 groups. Group I included patients with an increase in creatinine during hospitalization of <or=0.5 mg/dl. Group II included patients with an increase in creatinine of >0.5 mg/dl that resolved by discharge. Group III included patients with an increase in creatinine of >0.5 mg/dl that did not resolve. The primary end point was 6-month mortality from any cause. Patients in groups II and III had higher 6-month mortality rates (27% and 23%, respectively; both p<0.001) compared with patients in group I (7.4%). After adjustment for known risk factors, a transient increase in creatinine remained a significant independent predictor of 6-month mortality (odds ratio 2.07, 95% confidence interval 1.14 to 3.76), although a sustained increase in creatinine showed a trend (odds ratio 1.58, 95% confidence interval 0.68 to 3.70). In conclusion, independent of a history of renal insufficiency or increased admission creatinine, in-hospital worsening of renal function is an important risk factor for 6-month mortality in patients admitted with ACS. Furthermore, return to baseline function by discharge does not protect against this risk. These findings have implications for management of these high-risk patients.