OBJECTIVE: To evaluate the prognostic utility of multiple novel urinary biomarkers of renal injury when used alone, in pair-wise combination with an early delta serum creatinine (ΔS) term, and combined as a broad biomarker panel for the prediction of serious adverse outcomes that may reflect AKI in patients undergoing cardiac surgery. DESIGN: Post-hoc analysis of prospective observational study. SETTING: Academic medical center. PARTICIPANTS: 603 adults undergoing cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urinary cystatin-c, kidney injury molecule-1, chemokine (C-C motif) ligand 2 and interleukin-18 were measured at baseline and <1 hour, 3 hours and 18-24 hours after separation from cardiopulmonary bypass (CPB). ΔS was defined as the difference in S from baseline to first postoperative measure. The primary outcome of hospital mortality or renal replacement therapy occurred in 25 patients. Concordant elevation of any urinary biomarker measured 3 hours after CPB together with ΔS ≥0 mg.dL provided excellent early risk stratification for the primary outcome (OR ≥15.1, 95% CI 4.1-55.4). Combining four urinary biomarkers together with ΔS and neutrophil gelatinase-associated lipocalin, previously reported from the same cohort, to provide a 6-point AKI risk score enabled early identification of patients reaching the primary outcome (ROC 0.86, 95% CI 0.79-0.92) with potentially useful sensitivity and specificity at varied cut-points. CONCLUSIONS: Combining novel urinary biomarkers of renal injury with a creatinine-based metric soon after cardiac surgery provided excellent prognostic utility for serious adverse outcomes. Future studies are required to confirm these findings and determine optimal biomarker combinations for cost-effective risk stratification.