To establish a mathematical model of middle ear gas pressure regulation and to discuss potential implications for pathophysiology-oriented theoretical approach to middle ear surgery, with particular attention to mastoid obliteration. Numerous studies support that small mastoid volume is associated with cholesteatoma. Latest studies show that mastoid obliteration is an effective technique to lower the recurrence rate in these ears. A mathematical model was used to predict the development of gas pressure balance in the function of different middle ear volumes (VME), considering normal and dysfunctional Eustachian tube. Published data as gas pressure input values and our 3D CT reconstruction data in healthy and pathologic middle ears of children were applied. The model predicted ≤6.66 daPa pressure fluctuations in VME ≥3 ml, compared to ≥16 daPa of a VME ≤1 ml at perfect ET function, because of the different pressure change rate and pressure buffer effect of the MEs. Substantially larger fluctuations can be expected in a VME <3 ml with malfunctioning ET. Modeling mastoid obliteration predicts similar pressure fluctuations to a VME ≥3 ml resulting from elimination of gas exchange surface. Pressure change is faster in smaller MEs than in larger ones. Healthy MEs between 3 and 6 ml are very sensitive to the duration of a potential ET dysfunction to develop ME pathology. In MEs with poor mastoid pneumatization and dysfunctional ET, typical in cholesteatoma cases, mastoid obliteration as surgical reduction of mucosal surface for gas exchange can improve ME gas pressure balance resulting in better long-term outcome.