© 2019 Author(s).Objective To determine the cost-effectiveness of selective digestive decontamination (SDD) as compared to selective oropharyngeal decontamination (SOD) in intensive care units (ICUs) with low levels of antimicrobial resistance. Design Post-hoc analysis of a previously performed individual patient data meta-analysis of two cluster-randomised cross-over trials. Setting 24 ICUs in the Netherlands. Participants 12 952 ICU patients who were treated with ≥1 dose of SDD (n=6720) or SOD (n=6232). Interventions SDD versus SOD. Primary and secondary outcome measures The incremental cost-effectiveness ratio (ICER; ie, costs to prevent one in-hospital death) was calculated by comparing differences in direct healthcare costs and in-hospital mortality of patients treated with SDD versus SOD. A willingness-to-pay curve was plotted to reflect the probability of cost-effectiveness of SDD for a range of different values of maximum costs per prevented in-hospital death. Results The ICER resulting from the fixed-effect meta-analysis, adjusted for clustering and differences in baseline characteristics, showed that SDD significantly reduced in-hospital mortality (adjusted absolute risk reduction 0.0195, 95% CI 0.0050 to 0.0338) with no difference in costs (adjusted cost difference €62 in favour of SDD, 95% CI-€1079 to €935). Thus, SDD yielded significantly lower in-hospital mortality and comparable costs as compared with SOD. At a willingness-to-pay value of €33 633 per one prevented in-hospital death, SDD had a probability of 90.0% to be cost-effective as compared with SOD. Conclusion In Dutch ICUs, SDD has a very high probability of cost-effectiveness as compared to SOD. These data support the implementation of SDD in settings with low levels of antimicrobial resistance.