Secretion of pulmonary surfactant that maintains low surface tension within the lung is primarily mediated by mechanical stretching of alveolar epithelial type II (AEII) cells. We have shown that guinea pigs ventilated with random variations in frequency and tidal volume had significantly larger pools of surfactant in the lung than animals ventilated in a monotonous manner. Here we test the hypothesis that variable stretch patterns imparted on the AEII cells results in enhanced surfactant secretion. AEII cells isolated from rat lungs were exposed to equi-biaxial strains of 12.5%, 25% or 50% change in surface area (SA) at 3 cycles/min for 15, 30 or 60 min. [³H]-labeled phoshatidylcholine (PC) release and cell viability were measured 60 min following the onset of stretch. While secretion increased following 15 min stretch at 50% SA and 30 min stretch at 12.5% SA, 60 min of cyclic stretch diminished surfactant secretion regardless of strain. When cells were stretched using a variable strain profile in which the amplitude of each stretch was randomly pulled from a uniform distribution, surfactant secretion was enhanced both at 25% and 50% mean SA with no additional cell injury. Furthermore, at 50% mean SA, there was an optimum level of variability that maximized secretion implying that mechanotransduction in these cells exhibits a phenomenon similar to stochastic resonance. These results suggest that application of variable stretch may enhance surfactant secretion, possibly reducing the risk of ventilator-induced lung injury. Variable stretch-induced mechanotransduction may also have implications for other areas of mechanobiology.