BACKGROUND: Reliable and accurate measurement of creatinine is essential for the estimation of kidney function (eGFR) and for survival prediction with the model of the end-stage liver disease (MELD) score. Bilirubin interference is considered an important interference of Jaffe creatinine assays; the enzymatic assay is also affected but less so. This study aimed to evaluate the comparability of the Jaffe and enzymatic creatinine methods and the impact of their discrepancy on clinical decision-making, particularly in the context of bilirubin interference. METHODS: We compared creatinine measurements from the Roche Jaffe Gen.2 (CREJ2) and Roche Creatinine Plus ver.2 (CREP2) assays using routine heparin plasma samples (n = 15,618). To estimate the clinical impact of bilirubin interference on these two assays, we evaluated our results in the context of eGFR-based staging of severity of kidney disease and the MELD score. RESULTS: The Roche Jaffe and enzymatic methods agree well for non-icteric samples with a mean relative bias of 3.97% but not in icteric samples. In samples with 5-20 mg/dl and 20-53 mg/dl bilirubin, the biases amounted to 10.9% and 43.4%, respectively. CONCLUSIONS: The Jaffe method's susceptibility to bilirubin interference, in comparison to the enzymatic assay, can result in higher MELD scores and can lead to an underestimation of kidney function.