Lack of precise, reliable and consistent measures of kidney dysfunction in acute kidney injury (AKI) causes uncertainty in the definition and management of this important condition and interferes with treatment standardization. Serum creatinine (SCr) remains a key determinant in the management of renal dysfunction. In disparate populations, previous authors suggested a paradoxical association between higher SCr and better survival. We set out to analyse the association between SCr at start of continuous renal replacement therapy (CRRT) and survival, and to postulate possible mechanisms for this association. We hypothesized that in this setting, the association of higher SCr with better survival may be determined by better nutrition, lesser volume overload or pre-existing chronic kidney disease (CKD). In multivariable logistic regression analysis utilizing multiple imputation parameter estimates, a higher SCr on admission and initiation of CRRT was monotonically associated with better survival (OR 1.438, 95% CI 1.034-1.999) controlling for selected covariates. Nutrition and volume adjustments did not affect the significance of SCr. Adjustment of the model by degree of admission CDK (MDRD formula) and severity of disease (Liano scores) respectively decreased or abolished the significance of SCr levels. In univariate analysis, larger weight gains and lower urine outputs were correlated with lower SCr. In this population of critically ill, virtually anuric patients with AKI, possible explanations of this counterintuitive association include first, that a higher SCr at start of CRRT is related to pre-existing CKD. CKD patients may require a lesser burden of disease to reach the point where CRRT is needed, and therefore have a better survival. Inversely, a lower SCr may be an indication of fluid overload, associated with worse survival. Our findings did not support a role of nutrition or muscle mass for this association. All these possibilities are worthy of thorough investigation, as findings will likely result in important changes in patient outcome.