OBJECTIVES: To compare homogeneous (HMM) versus non-homogeneous Markov models (NHMM) for cost-effectiveness analysis (CEA) of routine use of transparent dressings containing a chlorhexidine gluconate gel pad versus standard transparent dressings. The antimicrobial dressing protects central vascular accesses reducing the risk of catheter-related bloodstream infections (CRBSIs) in intensive care units (ICU).  The impact of the modeling approach on the decision of adopting antimicrobial dressings for critically-ill patients is discussed.   METHODS: Comparative clinical efficacy data from a multicentre randomized controlled trial (RCT) enrolling 1,879 patients and economical data from micro and macro-costing published studies were combined. The HMM and NHMM models were built separately using the same sources. The statistical unit was the ICU patient and the ICU perspective was chosen. Probabilistic sensitivity analyses (PSA) were conducted for both models for comparing the robustness of the CEA results.  RESULTS: The difference in clinical outcomes between each dressing strategies was statistically significant with both models while cost differences were not. The PSA with the NHMM resulted in 11.8 infections avoided per 1,000 patients (95%CI: [3.85; 19.64]) and a mean extra cost of €141 per patient (95%CI: [€-975; €1,258]) when using antimicrobial dressing. The PSA with the HMM resulted in 6.45 infections avoided per 1,000 patients (95%CI: [0.15; 12.75]) and the mean extra cost of €252 per patient (95%CI: [€-924; €1,428]).  CONCLUSIONS: The antimicrobial dressings are consistently more efficacious in preventing CRBSIs whatever the model used. The HMM is less sensitive to simulate the real life of the ICU patients. Regardless the model approach chosen the antimicrobial strategy is more efficacious than the comparator, but its probability of being cost-effective is comparatively reduced with the HMM. Time dependent approach (NHMM) seems to be better adapted to model rare events as CRBSIs.