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We tested whether CRP combined with the neutrophil-to-lymphocyte ratio (NLR) optimizes the prediction of infectious inflammation in hemodialysis patients. We conducted a retrospective study of 774 (mean age 71.1 ± 12.8 years, 35% women) hemodialysis patients from our institution, hospitalized between 2007 and 2021 for various reasons, with CRP levels available at admission. Infection was defined according to the International Sepsis Definition Conference criteria. An algorithm for the optimal CRP and NLR cutoff points for predicting infection was developed based on a decision tree analysis in the training cohort (n = 620) and then tested in the validation cohort (n = 154). A CRP level above 40 mg/L (obtained as the cutoff point in predicting infections in the training group, using ROC curve analysis) predicted an infection diagnosis with a sensitivity of 75% and a specificity of 76% with an odds ratio (OR) of 9.37 (95% CI: 5.36–16.39), according to a multivariate logistic regression analysis. Whereas, CRP levels above 23 mg/L together with an NLR above 9.7 predicted an infection diagnosis with a sensitivity of 69% and a specificity of 84% with an OR of 25.59 (95% CI: 9.73–67.31). All these results were reproduced in the validation set. Combined use of CRP with NLR may lower the CRP cutoff point in distinguishing between infectious and noninfectious inflammation in hemodialysis patients. [ABSTRACT FROM AUTHOR]