ObjectiveAntimicrobial stewardship (AMS) significantly reduces inappropriate antibiotic use and improves patient outcomes. In low-resource settings, AMS implementation may require concurrent strengthening of clinical microbiology capacity therefore additional investments. We assessed the cost-effectiveness of implementing AMS at Tikur Anbessa Specialised Hospital (TASH), a tertiary care hospital in Ethiopia.DesignWe developed a Markov cohort model to assess the cost–utility of pharmacist-led AMS with concurrent strengthening of laboratory capacity compared with usual care from a ‘restricted societal’ perspective. We used a lifetime time horizon and discounted health outcomes and cost at 3% annually. Data were extracted from a prospective study of bloodstream infections among patients hospitalised at TASH, supplemented by published literature. We assessed parameter uncertainty using deterministic and probabilistic sensitivity analyses.SettingTertiary care hospital in Ethiopia, with 800 beds and serves over half a million patients per year.PopulationCohort of adults and children inpatient population aged 19.8 years at baseline.InterventionLaboratory-supported pharmacist-led AMS compared with usual care. Usual care is defined as empirical initiation of antibiotic therapy in the absence of strong laboratory and AMS.Outcome measuresExpected life-years, quality-adjusted life-years (QALYs), costs (US$2018) and incremental cost-effectiveness ratio.ResultsLaboratory-supported AMS strategy dominated usual care, that is, AMS was associated with an expected incremental gain of 38.8 QALYs at lower expected cost (incremental cost savings:US$82 370) per 1000 patients compared with usual care. Findings were sensitive to medication cost, infection-associated mortality and AMS-associated mortality reduction. Probabilistic sensitivity analysis demonstrated that AMS programme was likely to be cost-effective at 100% of the simulation compared with usual care at 1%–51% of gross domestic product/capita.ConclusionOur study indicates that laboratory-supported pharmacist-led AMS can result in improved health outcomes and substantial healthcare cost savings, demonstrating its economic advantage in a tertiary care hospital despite greater upfront investments in a low-resource setting.