Background: House dust mite (HDM) allergy involves IgE and T _H2 responses to major and minor allergens. Less is known about the involvement of other immune pathways and the potential role of other HDM proteins in allergic disease. In this study, the association between HDM allergy and immune responses to the HDM proteome was investigated. Methods: The HDM proteome was represented by 40 purified recombinant HDM proteins (19 known allergens and 21 novel proteins). T-cell responses to HDM proteins were determined ex vivo and antibody responses (IgA, IgE, IgG and IgG4) were measured using micro arrays and basophil activation in 21 HDM allergic donors and 16 non-allergic controls. Changes in specific IgE, IgG and IgG4 during SQ HDM SLIT-Tablet immunotherapy was assessed in 38 subjects with allergic asthma. Results: HDM proteins were broadly immunogenic inducing comparable IgG, IgA, and non-T _H2 cytokine responses in both allergic and non-allergic individuals. Specific IgE, IgG4 and T _H2 cytokine responses were largely restricted to the allergic donors. IgE and IgG4 were primarily directed to known major allergens and overlapping in specificity whereas cellular T _H2 responses extended beyond the known HDM allergens. Individual proteins displayed distinct immunological profiles. HDM sublingual immunotherapy increased the levels of specific IgE and IgG4 but did not change the overall pattern of recognition. Conclusion: HDM proteins are highly immunogenic and give rise to complex patterns of immune recognition also in the absence of allergy. This has potential implications for the pathogenesis of HDM allergy and the mode of action of allergy immunotherapy.