Use of nontidal high-frequency oscillatory ventilation (HFOV) while the lungs are expanded by an imposed airway pressure (P(aw)) in neonates is increasingly based on evidence of decreased risk of lung injury. However, an objective method to optimize P(aw) is lacking. We measured lung volume changes (deltaV(L)[t]) via respiratory inductance plethysmography over a range of P(aw) settings in five piglets before and after lung lavage. These multiple deltaV(L)(t) were then simultaneously fit by an exponential rise to maximum model, deltaV(L)(t, P(aw)) = deltaV(L,max). (1 - e(-(t/tau))), where deltaV(L,max) was a sigmoidal function of P(aw) and tau varied with lung volume. Postlavage, the effective compliance (C(EFF) = deltaV(L,max)/P(aw)) was generally decreased, whereas tau increased, indicating a slower paced volume recruitment. Model-derived C(EFF)-deltaV(L,max) relationships were altered substantially after lavage and were sigmoidal with a bell-shaped derivative function. The maximum of its derivative corresponded to a favorable (or optimal) deltaV(L)/P(aw) where the maximal increase in compliance is achieved. In conclusion, C(EFF)-deltaV(L,max) data available from respiratory inductance plethysmography provided important insight to changes in lung mechanics. These also provided a basis of an objective method (1) to optimize P(aw) during HFOV and (2) to assess the efficacy of treatments and progression/regression of underlying disease in neonates managed with HFOV.