Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of proinflammatory mediators. In the mouse, mast cell protease-6 (mMCP-6) closely resembles the human version of mast cell tryptase, β-tryptase. The gene that encodes mMCP-6, Tpsb2, resides close by the H-2 complex (MHC gene) on chromosome 17. Thus, when the original mMCP-6 knockout mice were backcrossed to the BALB/c strain, these mice were carrying the 129/Sv haplotype of MHC (mMCP-6−/−/H-2bc). Further backcrossing yielded mMCP-6−/− mice with the BALB/c MHC locus. BALB/c mice were compared with mMCP-6−/− and mMCP-6−/−/H-2bc mice in a mouse model of experimental asthma. Although OVA-sensitized and challenged wild type mice displayed a striking airway hyperresponsiveness (AHR), mMCP-6−/− mice had less AHR that was comparable with that of mMCP-6−/−/H-2bc mice, suggesting that mMCP-6 is required for a full-blown AHR. The mMCP-6−/−/H-2bc mice had strikingly reduced lung inflammation, IgE responses, and Th2 cell responses upon sensitization and challenge, whereas the mMCP-6−/− mice responded similarly to the wild type mice but with a minor decrease in bronchoalveolar lavage eosinophils. These findings suggest that inflammatory Th2 responses are highly dependent on the MHC-haplotype and that they can develop essentially independently of mMCP-6, whereas mMCP-6 plays a key role in the development of AHR.