Rationale: Airways hyper-responsiveness (AHR) is a hallmark feature of asthma, and can be caused by various disparate mechanisms. Mouse models of AHR have been useful for studying these mechanisms in isolation, but such models still typically do not exhibit the same degree of AHR as seen in severe human asthma. We hypothesized that more severe AHR in mice could be achieved by imbuing them with more than one mechanism of AHR. Objectives: We sought to determine if the airway wall thickening accompanying allergic inflammation and the exaggerated smooth muscle shortening induced by intra-tracheal cationic protein could act together to produce a severe form of AHR. Methods: We used the forced oscillation technique to measure methacholine responsiveness in BALB/c mice that had been sensitized and challenged with ovalbumin (ova) followed by an intra-tracheal instillation of the poly-L-lysine (PLL). Measurements and Main Results: We found that both ova and PLL treatment alone caused moderate levels of AHR. When the two treatments were combined, however, they synergized in terms of their effect on lung stiffness to an extent that could even be fatal, reflecting a significantly enhanced level of airway closure. Conclusions: Our results suggest that mechanistic synergy between airway wall thickening and exaggerated smooth muscle shortening produces a more germane mouse model of asthma that may have particular relevance to the pathophysiology of the acute severe asthma exacerbation.