Pasteurella multocida is a bacterial pathogen that causes rhinitis (snuffles), pneumonia, otitis media, septicemia, metritis, and death in domestic rabbits. Currently, there are no effective vaccines to prevent infection by this organism. Subcutaneous (s.c.) immunization with either exotoxin or thiocyanate extracts of P. multocida induces partial protection in rabbits. Since disease begins at mucosal sites, induction of local immunity may be important in preventing systemic disease. Little is known concerning the efficacy of intranasal (i.n.) administration of these antigens in inducing protective mucosal immunity to P. multocida in rabbits. The purpose of this study was twofold: (i) to investigate the effectiveness of vaccination with purified P. multocida toxin (PMT) and a potassium thiocyanate extract of P. multocida (CN) in combination and (ii) to evaluate the efficacy of administration of these antigens i.n. versus s.c. Forty-eight rabbits were randomly divided into eight different treatment groups. Rabbits received either one or both antigens by either s.c. or i.n. administration. Following vaccination, each group received an i.n. challenge of P. multocida. Rabbits vaccinated with both antigens i.n. or s.c. had a 100% survival rate, few or no bacteria in the liver and lungs, high serum immunoglobulin G (IgG) and IgM antibody titers, and significant numbers of IgG antibody-secreting cells (ASC) in the spleen and tracheobronchial lymph node. Rabbits vaccinated i.n. had significant nasal and bronchoalveolar lavage IgA antibody levels. Rabbits vaccinated with only one antigen, either PMT or CN, had lower antibody titers, moderate to severe liver and lung infections, and fewer ASC compared to rabbits receiving both antigens. Rabbits in the control groups had moderate to severe liver and lung infections. This study indicates that i.n. immunization with both PMT and CN induces an effective response against homologous P. multocida challenge.