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RATIONALE Several institutions have implemented phenobarbital-based pathways for the treatment of alcohol withdrawal syndrome. However, little is known about the care processes, effectiveness, and safety of phenobarbital-based pathways for intensive care unit patients. OBJECTIVES This study aimed to examine clinician acceptability and feasibility and patient outcomes after the implementation of a phenobarbital-based pathway for medical intensive care unit patients with severe alcohol withdrawal syndrome. METHODS We conducted a mixed methods study of a quality improvement intervention designed to improve workflow without deleterious effects on outcomes. We used semi-structured qualitative interviews and surveys of clinicians to assess acceptability and feasibility of the phenobarbital-based pathway and a previous benzodiazepine-based pathway. We used a non-inferiority interrupted-time-series analysis to compare mechanical ventilation rates before and after implementation among medical intensive care unit patients within an urban safety net hospital admitted with severe alcohol withdrawal. We explored several secondary outcomes including physical-restraint use and hospital length of stay. RESULTS Four themes related to clinician acceptability and feasibility of the phenobarbital-based pathway emerged: [1] designing a pathway that balanced standardization with clinical judgement promoted acceptability; [2] pathway simplicity promoted feasibility; [3] implementing pathway-driven care streamlined workflow; [4] ad hoc implementation strategies facilitated new pathway uptake. 233 and 252 patients were initiated on the benzodiazepine- and phenobarbital-based pathways, respectively. The rate of mechanical ventilation decreased from 17.1% to 12.9% after implementation of the phenobarbital-based pathway, with an adjusted mean difference of -4.9% (95% upper CI 0.7%) corresponding to a 95% upper limit relative change of 4%, below the a priori non-inferiority margin. Use of physical restraints decreased from 51.6% to 32.4% (mean difference -18.0%, 95% CI -26.4%, -9.7%) and hospital length of stay was shorter (8.6 days to 6.8 days; mean difference -1.8 days, 95% CI -3.4, -0.2 days) after implementation. CONCLUSIONS Clinicians felt that the phenobarbital-based pathway was more efficient and simpler to use, and patient mechanical ventilation rates were non-inferior compared to the previous benzodiazepine-based pathway for the treatment of severe alcohol withdrawal syndrome.