Abstract BACKGROUND AND AIMS Kidneys play a primary role in electrolyte homeostasis. The association between serum sodium level and mortality or the need for kidney replacement therapy during acute kidney injury has not been adequately explored. METHOD In this prospective cohort study, we enrolled patients admitted to the Civil Hospital of Guadalajara from August 2017 to March 2020. We divided patients into five groups based on the serum sodium level trajectories up to 10 days following hospitalization: (1) stable normonatremia (serum sodium 135 and 145 mEq/L), (2) fluctuating serum sodium levels (increased/decreased in and out of normonatremia), (3) uncorrected hyponatremia, (4) corrected hyponatremia and (5) uncorrected hypernatremia. We assessed the association of serum sodium trajectories with mortality and the need for kidney replacement therapy (secondary objective). RESULTS A total of 288 patients were included. The mean age was 55 ± 18 years, and 175 (60.7%) were male. Acute kidney injury stage 3 was present in 145 (50.4%). Kidney replacement therapy started in 72 (25%) patients, and 45 (15.6%) died. After adjusting for confounders, 10-day hospital mortality was significantly higher in group 5 {HR, 3.12; [95% confidence interval (95% CI) 1.05–9.24]; P = .03}, and kidney replacement therapy initiation was higher in group 3 (HR, 2.44; 95% CI 1.04– 5.70; P = .03) compared with group 1. CONCLUSION In our prospective cohort, most patients with acute kidney injury had alterations in serum sodium. Uncorrected hypernatremia was associated with death, and uncorrected hyponatremia was correlated with the need for kidney replacement therapy.