Nasal vaccination of mice with recombinant attenuated strains of Salmonella typhimurium is more efficient at inducing antibody responses than oral vaccination. However, mortality was observed when high doses [10(9) colony forming unit (CFU)], otherwise safe by the oral route, were administered. This observation was counterbalanced by the fact that nasal vaccination was still highly efficient with lower doses (10(6) CFU), which are inefficient by the oral route and this, without any incidents of mortality. Here, we further analyse in mice the effect of nasal vaccination with differently attenuated S. typhimurium strains expressing the Hepatitis B nucleocapsid (HBc). Surprisingly, as few as 100 CFU were sufficient to induce a maximal HBc specific antibody response, but only if the bacteria were inhaled. Furthermore, we observed no correlation between the inoculum dose and the number of surviving bacteria in cervical lymph nodes and spleen. Examination of lung sections revealed strong inflammation and bronchopneumonia 24 h after nasal vaccination with 10(8) CFU, while only minor signs of inflammation were detected transiently when 10(3) CFU or phosphate buffered saline (PBS) were administered. Our data suggest that the safety issue of nasal vaccination with low doses of the Salmonella vaccine strains should be addressed in humans, as it might be an efficient alternative to oral vaccination.