Purpose Critically ill patients are occasionally resistant to, or become intolerant of, standard sedating agents. We describe our experience using phenobarbital (PB) as an alternative sedative in a select cohort of patients. Methods Medical records of adult patients treated with PB for sedation were retrospectively reviewed. Patients receiving barbiturates for seizures, brain injury, or drug withdrawal protocols were excluded. Data are presented as mean ± standard deviation or median (range). Results Seven patients were treated with PB after failing standard medications due to refractory agitation (five patients) or propylene glycol toxicity (two patients). Patients were 35 ± 10-years-old, six were female (86%), APACHE II was 16 ± 5, ICU stay was 16 (8 to 88) days, and all seven patients survived. Four patients were initially sedated with lorazepam (mean daily dose = 163 mg), two with propofol (mean dose = 51 mcg/kg/min), and one with both. All seven received fentanyl for analgesia. Patients were switched to PB on ICU day-6 (3 to 50) with 240 (60 to 490) mg given the first day in divided doses. Subsequent doses were titrated to desired response, typically Sedation Agitation Scale (SAS) 3. PB was continued for 6 (3 to 21) days. Quality of sedation appeared similar when assessed with average SAS of 3.5 pre vs 3.7 post, as well as, by the absence of both oversedation (SAS less 3) and medical device removal. Hemodynamic derangements were not noted, and four patients were extubated while receiving PB. Conclusions PB provides adequate sedation and may be an alternative for patients intolerant or unresponsive to standard agents.