Background: High frequency (HF) oscillatory ventilation has been shown to improve CO2 clearance in premature infants. In a previous in vitro lung model with normal lung mechanics we demonstrated significantly improved CO2 washout by HF oscillation of bubble CPAP (BCPAP). Objective: To examine CO2 clearance in a premature infant lung model with abnormal lung mechanics via measurement of end-tidal CO2 levels (EtCO2) while connected to HF oscillated BCPAP. Design/Methods: A 40mL premature infant lung model with either: normal lung mechanics (NLM): compliance 1.0 mL/cmH2O, airway resistance 56 cmH2O/(L/s); or abnormal lung mechanics (ALM): compliance 0.5 mL/cmH2O, airway resistance 136 cmH2O/(L/s), was connected to BCPAP with HF oscillation at either 4,6,8,10 or 12 Hz. EtCO2 was measured at BCPAPs of 4,6 and 8 cmH2O and respiratory rates (RR) of 40,60 and 80 breaths/min and 6mL tidal volume. Results: HF oscillation decreased EtCO2 levels at all BCPAPs, RRs, and oscillation frequencies for both lung models. Overall mean±SD EtCO2 levels decreased (p<0.001) from non-oscillated baseline by 19.3±10.2% for NLM vs. 14.1±8.8% for ALM. CO2 clearance improved for both lung models (p<0.001) as a function of oscillation frequency and RR with greatest effectiveness at 40-60 breaths/min and HF at 8-12 Hz. Conclusions: In this in-vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO2 clearance as compared to non-oscillated BCPAP for both NLM and ALM. The significant improvement in CO2 clearance in an abnormal lung environment is an important step towards clinical testing of this novel respiratory support modality.