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Introduction: Interdialytic weight gain (IDWG) is crucial in the association between long interdialytic intervals and mortality in hemodialysis patients. The impact of IDWG on changes in residual kidney function (RKF) has not been evaluated thoroughly. This study examined the associations of IDWG in the long intervals (IDWGL) with mortality and rapid RKF decline. Methods: This retrospective cohort study included patients who initiated hemodialysis in the United States dialysis centers from 2007 to 2011. IDWGL was defined as IDWG in the two‐day break between dialysis sessions. This study examined the associations of seven categories of IDWGL (0% to <1%, 1% to <2%, 2% to <3% [reference], 3% to <4%, 4% to <5%, 5% to <6%, and ≥6%) with mortality using Cox regression models and rapid decline of renal urea clearance (KRU) using logistic regression models. The continuous relationships between IDWGL and study outcomes were investigated using restricted cubic spline analyses. Findings: Mortality and rapid RKF decline were assessed in 35,225 and 6425 patients, respectively. Higher IDWGL categories were linked to increased risk of adverse outcomes. The multivariate adjusted hazard ratios (95% confidence intervals) of all‐cause mortality for 3% to <4%, 4% to <5%, 5% to <6%, and ≥6% IDWGL were 1.09 (1.02–1.16), 1.14 (1.06–1.22), 1.16 (1.06–1.28), and 1.25 (1.13–1.37), respectively. The multivariate adjusted odds ratios (95% confidence intervals) of rapid decline of KRU for 3% to <4%, 4% to <5%, 5% to <6%, and ≥6% IDWGL were 1.03 (0.90–1.19), 1.29 (1.08–1.55), 1.17 (0.92–1.49), and 1.48 (1.13–1.95), respectively. When IDWGL exceeded 2%, the hazard ratios of mortality and the odds ratios of rapid KRU decline continuously increased. Discussion: Higher IDWGL was incrementally associated with higher mortality risk and rapid KRU decline. IDWGL level over 2% was linked to higher risk of adverse outcomes. Therefore, IDWGL may be utilized as a risk parameter for mortality and RKF decline. [ABSTRACT FROM AUTHOR]