ABSTRACT Background Dependence on gamma-hydroxybutyrate (GHB) is an emerging substance use disorder which can be life-threatening in overdose and withdrawal. The aim of this study was to describe rising GHB-related hospitalizations amidst the ongoing COVID-19 pandemic. Methods A retrospective consecutive case series of adults admitted to hospitals in South Western Sydney Local Health District was identified with clinical coding of GHB-related disorder between March 20 2019 and March 20 2021. Morbidity outcomes and multivariable Kaplan–Meier survival analysis on length of hospital stay were described. Results Sixty-nine of 84 included admissions, (82%) occurred in the 12 months following COVID-19 related border closure. Of 47 admissions for withdrawal, fifteen of 47 (32%) required intensive care, 6 (13%) intubation, 4 (9%) one-to-one ward observation, and 8 (17%) emergency calls for agitated delirium, fall, or seizure. Five cofactors were associated with longer hospital stay in the multivariable analysis: age 30 or older (p < .05), 6 months of regular GHB use (p < .01), and elective admission (p < .05), and diagnosis of psychosis rather than withdrawal (p < .05) or overdose (p < .001). Conclusions Development of a validated GHB withdrawal severity scale based on these risk factors could help identify patients requiring close monitoring for complicated withdrawal and escalation of care.