: Across Southeast Asia, declining malaria incidence poses a challenge for healthcare providers, in how best to manage the vast majority of patients with febrile illnesses who have a negative malaria test. In rural regions, where the majority of the population reside, empirical treatment guidelines derived from central urban hospitals are often of limited relevance. In these settings, health workers with limited training deliver care, often without any laboratory diagnostic support. In this paper, we model the impact of point-of-care C-reactive protein testing to inform the decision to prescribe antibiotics and regional surveillance data to inform antibiotic selection, and then simulate the subsequent impact on mortality from febrile illnesses, rooted in the real-world context of rural Savannakhet province, southern Laos. : Our model simulates 100 scenarios with varying quarterly incidence of six key pathogens known to be prevalent in rural Laos. In the simulations, community health workers either prescribe antibiotics in-line with current practice as documented in health facilities in rural Laos, or with the aid of the two interventions. We provide cost-effectiveness estimates for each strategy alone and then for an integrated approach using both interventions. : We find that each strategy is predicted to be highly cost-effective, and that the combined approach is predicted to result in the biggest reduction in mortality (averting a predicted 510 deaths per year in rural Savannakhet, a 28% reduction compared to standard practice) and is highly cost-effective, with an incremental cost-effectiveness ratio of just $66 per disability-adjusted life year averted. : Substantial seasonal variation in the predicted optimal empirical antibiotic treatment for febrile illness highlights the benefits of up-to-date information on regional causes of fever. In this modelling analysis, an integrated system incorporating point-of-care host biomarker testing and regional surveillance data appears highly cost-effective, and may warrant piloting in a real-life setting.