Background: The optimal time to initiate renal replacement therapy (RRT) in cardiac surgery-associated acute kidney injury (CSA-AKI) is unknown. Evidence suggests that the early use of RRT in critically ill patients is associated with improved outcomes. We studied the effects of time to initiation of RRT on outcome in patients with CSA-AKI. Methods: This was a retrospective observational multicenter study (24 Spanish hospitals). We analyzed data on 203 patients who required RRT after cardiac surgery in 2007. The cohort was divided into 2 groups based on the time at which RRT was initiated: in the early RRT group, therapy was initiated within the first 3 days after cardiac surgery; in the late group, RRT was begun after the 3rd day. Multivariate nonconditional logistic and linear regression models were used to adjust for potential confounders. Results: In-hospital mortality was significantly higher in the late RRT group compared with early RRT patients (80.4 vs. 53.2%; p < 0.001; adjusted odds ratio of 4.1, 95% CI: 1.6–10.0). Also, patients in the late RRT group had longer adjusted hospital stays by 11.6 days (95% CI: 1.4–21.9) and higher adjusted percentage increases in creatinine at discharge compared with baseline by 67.7% (95% CI: 28.5–106.4). Conclusions: Patients who undergo early initiation of RRT after CSA-AKI have improved survival rates and renal function at discharge and decreased lengths of hospital stay.