Nontypeable Haemophilus influenzae (NTHi) is associated with significant morbidity in both children and adults, causing localized respiratory tract disease such as acute otitis media, sinusitis, and pneumonia and accounting for occasional serious invasive disease. The pathogenesis of NTHi disease begins with colonization of the upper respiratory tract, followed by contiguous spread to sites of infection. Existing strategies to prevent NTHi disease are limited to adenoidectomy and antibiotic prophylaxis; unfortunately, these approaches are relevant only for recurrent otitis media and often associated with short-term and long-term complications. Consequently, there is interest in developing a vaccine to prevent nasopharyngeal carriage, a prerequisite for disease. Among potential vaccine antigens is the High Molecular Weight (HMW) family of outer membrane adhesins, which includes HMW1 and HMW2. In this work, we evaluated the ability of HMW1 and HMW2 to stimulate an immune response and protection against NTHi nasopharyngeal colonization. We demonstrated that intranasal immunization with HMW1 and HMW2 is highly immunostimulatory and protects mice against colonization by heterologous strains of NTHi. Elements of this protective immunity include both a strain-specific antibody response and broad-acting Th17 response. To study the strain specificity of the antibody response in greater depth, we compared the immune response to HMW1 and HMW2 from the same strain and from heterologous strains. Despite the high conservation of the HMW1 and HMW2 adhesins, these proteins show significant immunological differences and consistently produce strain-specific antibody responses. We found that these differences may be caused by protein glycosylation. Given the role of protein glycosylation in shaping the immunogenicity of the HMW1 and HMW2 adhesins, we investigated the mechanisms that influence HMW1 glycosylation by the HMW1C glycosyltransferase. We found that while there is no clear signal shaping their interaction, the stoichiometry between HMW1 and HMW1C is critical to shaping glycosylation specificity. Collectively, this body of work highlights the potential for HMW1 and HMW2 as vaccine antigens and reveals important insights into how these adhesins can stimulate protective immunity.