Background and objectives: Hypernatremia can be community or hospital-acquired, and there may be specific factors unique to the hospital environment, such as intravenous fluid treatment, which contribute to hypernatremia. The aim of this study was to determine the factors associated with the progression from moderate to severe hospital-acquired hypernatremia among patients admitted under general medicine. Materials and Methods: In this retrospective, single-center cohort study (2012 to 2017), we used ICD-10 coding and medical records to identify adult patients who developed moderate hypernatremia and followed them for progression to severe hypernatremia. We profiled the serum biochemistry and the volume and composition of prescribed intravenous fluids. We applied logistic regression to determine the factors associated with the progression to severe hypernatremia, using the patients with moderate hypernatremia as reference. Results: Of the 180 medical inpatients (median age of 81 years) with moderate hospital-acquired hypernatremia, 9.4% progressed to severe hypernatremia. Normal saline comprised 76% of intravenous fluid volume administered prior to onset of moderate hypernatremia. After the onset, 38% of fluid volume prescribed remained normal saline. The factors independently associated with progression to severe hypernatremia included chronic kidney disease stage (odds ratio 2.38, 95% CI: 1.26–4.50, P = 0.008) and serum creatinine increase (per 10 µmol/L, OR 1.29, 95% CI: 1.07–1.57, P = 0.009). Conclusions: Patients with chronic kidney disease and acute kidney injury may have an increased risk of severe hospital-acquired hypernatremia.