Pulmonary surfactant (PS) preparations based mainly on bovine or porcine extracts are commonly administered to patients with neonatal respiratory distress syndrome (NRDS) for therapy. The preparations are sufficiently effective to treat NRDS; however, they are associated with a risk of infection and involve costly purification procedures to achieve batch-to-batch reproducibility. Therefore, we investigated the mechanism and interfacial behavior of synthetic PS preparations containing a mimicking peptide (KLLKLLLKLWLKLLKLLL, Hel 13-5). In particular, a hybrid PS formulation with fluorinated amphiphiles is reported from the perspective of surface chemistry. Fluorinated amphiphiles are characterized by exceptional chemical and biological inertness, high oxygen-dissolving capacity, low surface tension, excellent spreading ability, and high fluidity. These properties are superior to those for the corresponding hydrocarbon analogs. Indeed, a small amount of fluorinated long-chain alcohols enhances the effectiveness of the model PS preparation for in vitro pulmonary functions. Moreover, the mode of the improved efficacy differs depending on the hydrophobic chain length in the alcohols. For alcohols with a short fluorocarbon (FC) chain, the monolayer phase of the model PS preparation remains disordered (fluidization). However, the addition of alcohols containing a long FC chain reduces the disordered/ordered phase transition pressure and the growth of ordered domains of the monolayer (condensation). Furthermore, repeated compression-expansion isotherms of the monolayers, which can simulate respiration in the lung, suggest irreversible elimination of the short-FC alcohol into the subphase and enhancement of the squeeze-out phenomenon of certain PS components by solid-like monolayer formation induced by the long-FC alcohol. We demonstrated that fluorinated amphiphiles may be used as additives for synthetic or commercial PS preparations for RDS treatment.