To report use trends of plasma exchange (PLEX) as well as sociodemographic and medical comorbidities associated with PLEX in the United States. Retrospective cross-sectional study. Adult patients (≥ 18 years) admitted for inpatient hospitalization with a primary diagnosis of optic neuritis (ON). Data from the National Inpatient Sample database was compiled to assess PLEX use rates between 2000 and 2020. The cohorts of patients receiving PLEX versus not receiving PLEX were analyzed between quarter 4 of 2015 through 2020 (International Classification of Diseases, Tenth Revision [ICD-10], only) for patient sociodemographic variables, medical diagnoses, insurance types, hospital characteristics, cause of disease, time to therapy, length of stay (LOS), and total charges incurred. Incidence of ON, incidence of PLEX, demographics, diagnoses associated with PLEX therapy, total charges, and LOS. From 2000 through 2020, 11 209 patients hospitalized with a primary diagnosis of ON were identified, with a significant majority managed at urban teaching hospitals. Use of PLEX increased steadily over 2 decades from 0.63% to 5.46%. Use was greatest in the western United States and least in the eastern United States. In the subset of ICD-10 cases, 3215 patients were identified. The median time to therapy of PLEX was 1 day after admission, and PLEX use was highest in patients with neuromyelitis optica spectrum disorder (NMOSD) (21.21%) and lowest in multiple sclerosis-associated ON (3.80%). Use of PLEX was associated with significantly longer LOS and higher total charges incurred. Medical comorbidities associated with PLEX included adverse reaction to glucocorticoids (adjusted odds ratio [aOR], 31.50), hemiplegia (aOR, 28.48), neuralgia (aOR, 4.81), optic atrophy (aOR, 3.74), paralytic strabismus (aOR, 2.36), and psoriasis (aOR, 1.76). Over the last 2 decades in the United States, PLEX therapy for ON has increased, with the highest use in the western United States and for patients with the diagnosis NMOSD ON. The author(s) have no proprietary or commercial interest in any materials discussed in this article.