To develop new treatment possibilities for patients with severe lung diseases it is crucial to understand the lung function on an alveolar level. Optical coherence tomography (OCT) in combination with intravital microscopy (IVM) are used for imaging subpleural alveoli in animal models to gain information about dynamic and morphological changes of lung tissue during mechanical ventilation. The image content suitable for further analysis is influenced by image artifacts caused by scattering, refraction, reflection, and absorbance. Because the refractive index varies with each air-tissue interface in lung tissue, these effects decrease OCT image quality exceedingly. The quality of OCT images can be increased when the refractive index inside the alveoli is matched to the one of tissue via liquid-filling. Thereby, scattering loss can be decreased and higher penetration depth and tissue contrast can be achieved. To use the advantages of liquid-filling for in vivo imaging of small rodent lungs, a suitable breathing fluid (perfluorodecalin) and a special liquid respirator are necessary. Here we show the effect of liquid-filling on OCT and IVM image quality of subpleural alveoli in a mouse model.