BACKGROUND: Burkitt Lymphoma (BL) is a prevalent and highly aggressive childhood cancer in sub-Saharan Africa (SSA). Outcomes are poor, due in part to delays or inaccuracies in diagnosis. Liquid biopsy (sequencing circulating tumour DNA from blood) is an alternative approach that is non-invasive and offers potential for a highly specific, rapid diagnosis, which could improve outcomes through earlier access to correct treatment. Diagnosis by liquid biopsy has undergone validation in SSA. However, evidence on its economic value is needed, especially in limited-resource settings. We present a cost-utility analysis comparing liquid biopsy with conventional local histopathology for the diagnosis of paediatric BL in Tanzania. METHODS: A cost-utility model was constructed to compare the costs and effects of the alternative diagnostic approaches from a Tanzanian healthcare provider perspective, over a lifetime horizon. For the liquid biopsy, we assumed testing at the patient's first contact with healthcare, resulting in earlier diagnosis. Resource use and outcome data were taken from the Aggressive Infection-Related East Africa Lymphoma study. Health outcomes were measured in Disability-Adjusted Life Years (DALYs). Costs and outcomes were discounted at 5%. Probabilistic and univariate sensitivity analyses and scenario analysis were conducted. RESULTS: Diagnosis by liquid biopsy results in a reduced burden of 9.4 DALYs per patient compared to 10.5 for histopathology (difference 1.11 DALYs, 95% confidence interval 0.13-2.06), and per-patient costs are $1978 higher (95% CI $1299-2840), due to greater diagnosis costs. The incremental cost-effectiveness ratio (ICER) is $1778 per DALY averted. Probabilistic sensitivity analysis indicates that liquid biopsy is more likely to be cost-effective than pathology, at any threshold above $1890/DALY averted. The ICER is sensitive to assumptions regarding the extent of disease advancement at the earlier diagnosis, and to discount rate and diagnosis costs. CONCLUSIONS: Diagnosis by liquid biopsy could be cost-effective when used to accelerate diagnosis of BL in children and young adults in Tanzania, depending on when it is implemented in the patient journey, model assumptions and the decision threshold chosen. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR202204822312651, registered on 14th April 2022.