An experimental model of Haemophilus parasuis infection was developed in cesarean derived, colostrum deprived (CDCD) swine. Inoculated pigs developed clinical signs of inappetence, reluctance to move, lameness, and a serous nasal discharge. Macroscopic findings consisted of fibrinopurulent polyserositis and polyarthritis. Microscopic lesions included a mild purulent rhinitis, marked fibrinopurulent synovitis, and moderate fibrinopurulent pleuritis and peritonitis. H. parasuis was initially recovered from the nasal cavity and recovered from the blood and systemic serosal sites at later time points. Results of this study suggested that this model resulted in clinical signs and lesions consistent with field cases of H. parasuis infection;In subsequent studies, the CDCD swine model and an agar embedded nasal mucosal explant system were used to investigate mucosal colonization. In CDCD pigs, H. parasuis was readily recovered from the middle nasal cavity and not recovered from the tonsil. Antigens of H. parasuis were present in sections from the middle and caudal nasal cavity. Light microscopic lesions consisted of submucosal and intraepithelial infiltrates of neutrophils and infrequent, patchy loss of cilia. Ultrastructural changes in the nasal mucosal epithelial cells included cell protrusion, loss of cilia, and dilation of the cytocavitary network. Bacteria were found in an amorphous material at the apical mucosal surface or between cilia. In the nasal mucosal explant system, control explants maintained ciliary vigor for up to 72 hours. Infected explants had decreased ciliary vigor at 2 and 4 hours post inoculation and increased mucus accumulation. Light microscopic changes consisted of minimal epithelial cell protrusion. Ultrastructural changes in infected explants included cell protrusion, loss of cilia, and mitochondrial swelling. These studies demonstrate that H. parasuis induces functional and structural damage of the nasal mucosa. H. parasuis may initially associate with a mucus layer and induce damage to the underlying mucosa by release of one or more toxic compounds. This cellular damage compromises the mucosal barrier and may lead to invasion and systemic spread of infection.