To develop a Pseudomonas aeruginosa vaccine that allows the host immune system to select the antigens, we hypothesized that dendritic cells (DC) pulsed with P. aeruginosa would induce protective immunity against pulmonary infections with P. aeruginosa. Incubation of murine bone marrow-derived DC with P. aeruginosa in vitro led to uptake of P. aeruginosa and activation of the DC. Spleen-derived CD4⁺ cells from mice immunized withP. aeruginosa-pulsed DC showed increased proliferation, demonstrating that DC pulsed with P. aeruginosa were capable of eliciting a P. aeruginosa-specific immune response. To evaluate if P. aeruginosa-pulsed DC can induce protective immunity against P. aeruginosapulmonary infection, DC incubated with P. aeruginosa in vitro were administered systemically to syngeneic mice, and the mice were then challenged by intrapulmonary infection with P. aeruginosa (5 × 10⁴ CFU/mouse) 13 days later. Unimmunized control mice and mice who had previously received naive DC or DC stimulated with lipopolysaccharide or Escherichia coli died within 72 h. In contrast, 45% of mice receivingP. aeruginosa-pulsed DC demonstrated prolonged survival (>14 days). Finally, DC-pulsed with heat-inactivated P. aeruginosa protected CD8^−/− but not CD4^−/− mice, demonstrating that CD4⁺ T cells were required for the DC pulsed with P. aeruginosa to induce protective immunity.