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Background Early infant diagnosis (EID) for HIV-exposed infants is essential due to high mortality during the first months of their lives. In Conakry (Guinea), timely EID is difficult as traffic congestion prevents the rapid transport of blood samples to the central laboratory. We investigated the cost-effectiveness of transporting EID blood samples by unmanned aerial vehicles (UAV), also known as drones.Methods and findings Using Monte Carlo simulations, we conducted a cost-effectiveness comparative analysis between EID blood samples transportation by on-demand UAV transportation versus the baseline scenario (ie, van with irregular collection schedules) and compared with a hypothetic on-demand motorcycle transportation system. Incremental cost-effectiveness ratio (ICER) per life-year gained was computed. Simulation models included parameters such as consultation timing (eg, time of arrival), motorcycle and UAV characteristics, weather and traffic conditions. Over the 5-year period programme, the UAV and motorcycle strategies were able to save a cumulative additional 834.8 life-years (585.1–1084.5) and 794.7 life-years (550.3–1039.0), respectively, compared with the baseline scenario. The ICER per life-year gained found were US$535 for the UAV strategy versus baseline scenario, US$504 for the motorcycle strategy versus baseline scenario and US$1137 per additional life-year gained for the UAV versus motorcycle strategy. Respectively, those ICERs represented 44.8%, 42.2% and 95.2% of the national gross domestic product (GDP) per capita in Guinea—that is, US$1194.Conclusion Compared with the baseline strategy, both transportation of EID blood samples by UAVs or motorcycles had a cost per additional life-year gained below half of the national GDP per capita and could be seen as cost-effective in Conakry. A UAV strategy can save more lives than a motorcycle one although the cost needed per additional life-year gained might need to consider alongside budget impact and feasibility considerations.