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To practically determine the effect of chloride (Cl) on the acid-base status, four approaches are currently used: accepted ranges of serum Cl values; Cl corrections; the serum Cl/Na ratio; and the serum Na-Cl difference. However, these approaches are governed by different concepts. Our aim is to investigate which approach to the evaluation of the effect of Cl is the best. In this retrospective cohort study, 2529 critically ill patients who were admitted to the tertiary care unit between 2011 and 2018 were retrospectively evaluated. The effects of Cl on the acid-base status according to each evaluative approach were validated by the standard base excess (SBE) and apparent strong ion difference (SIDa). To clearly demonstrate only the effects of Cl on the acid-base status, a subgroup that included patients with normal lactate, albumin and SIG values was created. To compare approaches, kappa and a linear regression model for all patients and Bland-Altman test for a subgroup were used. In both the entire cohort and the subgroup, correlations among BECl, SIDa and SBE were stronger than those for other approaches (r = 0.94 r = 0.98 and r = 0.96 respectively). Only BECl had acceptable limits of agreement with SBE in the subgroup (bias: 0.5 mmol L-1) In the linear regression model, only BECl in all the Cl evaluation approaches was significantly related to the SBE. For the evaluation of the effect of chloride on the acid-base status, BECl is a better approach than accepted ranges of serum Cl values, Cl corrections and the Cl/Na ratio., Competing Interests: The authors have declared that no competing interests exist.