OBJECTIVES: To analyze the costs of macrolides use compared to cephalosporines for treatment of Acute Bacterial Sinusitis (ABSs) in the era of increasing resistance to Streptococcus pneumoniae.  METHODS: We used a decision analysis model (TreeAge Pro 2013) to perform a cost-minimization and sensitivity analysis to determine what level of macrolide resistance in a community would trigger cephalosporine use. Costs and clinical outcomes of ABSs were extracted from a systematic review of the literature and official local databases. Clinical response was derived from prospective clinical trials, investigations and from clinical experts experience, were we had ≤1 source.  RESULTS: We have found that the mean cost of empirical treatment with macrolides for ABSs was 79 EUR when community S. pneumoniae resistance was at 0%; 77 EUR at 10%; 82 EUR at 20% and 88 EUR at 30%. Cephalosporines were found to be cost-minimizing when the prevalence of macrolide resistance to S. pneumoniae exceeded 15%. Sensitivity analysis variables that had a significant impact on our cost-minimization threshold included proportion of macrolide resistance to S. pneumoniae, cost of antibiotics and probabilities of clinical cure with antibiotics.   CONCLUSIONS: We believe we have performed the first cost-based model and sensitivity analysis to determine what level of macrolide resistance in the community could trigger a switch of empirical therapy for ABSs from macrolides to cephalosporines in Slovakia. Our investigation is to our knowledge also locally the first to employ decision analysis to explore the relationship between antimicrobial resistance and clinical decision making in ABSs. From a payer perspective, cephalosporines appears to be a reasonable alternative to macrolides for empirical treatment of ABSs, especially given the current prevalence of macrolides resistance among S. pneumoniae in community that reached 30% level, nationwide.