To assess the effect of intravenous chloride load on prognosis in intensive care unit (ICU) patients with different initial serum chloride levels. Participants from the Medical Information Mart for Intensive Care IV database were divided into low, normal (>100 and ≤110 mEq/L), and high chloride groups according to initial chloride levels. Records of intravenous fluids were extracted to calculated the volume adjusted chloride load (VACL) and VACL per body weight (VACL-W). The associations of VACL, VACL-W, and changes in serum chloride concentration (ΔCl) with mortalities were investigated in different initial chloride groups. Respectively, 4593 (20.9%), 13,364 (60.9%), and 3978 (18.1%) patients had a low, normal, and high initial chloride level. Interactions were found between initial chloride levels and VACL, VACL-W, and ΔCl on mortality risks. In normal and high chloride groups, increased VACL, VACL-W, and ΔCl were associated with higher ICU and hospital mortalities. However, in the low chloride group, multivariable models found no associations between VACL, VACL-W, or ΔCl with mortalities. High chloride load and increased serum chloride level were associated with poor outcomes in patients with normal or high initial chloride levels, but not in those with a low initial chloride level.