Protein D (PD) is a highly conserved 42 kDa surface lipoprotein found in all Haemophilus influenzae, including nontypeable (NT) H. influenzae. PD is involved in the pathogenesis of respiratory tract infections, in the context of which it has been shown to impair ciliary function in a human nasopharyngeal tissue culture model and to augment the capacity to cause otitis media in rats. A likely mechanism indicating that PD is a virulence factor is its glycerophosphodiesterase activity, which leads to the release of phosphorylcholine from host epithelial cells. PD has been demonstrated to be a promising vaccine candidate against experimental NT H. influenzae infection. Rats vaccinated with PD cleared NT H. influenzae better after middle ear and pulmonary bacterial challenge, and chinchillas vaccinated with PD showed significant protection against NT H. influenzae-dependent acute otitis media. In a clinical trial involving children, PD was used as an antigenically active carrier protein in an 11-valent pneumococcal conjugate investigational vaccine; significant protection was achieved against acute otitis media not only caused by pneumococci but also caused by NT H. influenzae. This may have great clinical implications, because PD is the first NT H. influenzae antigen that has induced protective responses in humans.