A ribosomal vaccine of Pseudomonas aeruginosa and a vaccine containing purified lipopolysaccharide (LPS) were compared with respect to their capacity to protect mice against a lethal challenge with P. aeruginosa. The route of vaccination appeared to be important for the protective activity of the ribosomal vaccine. Optimal protection was measured if both the immunizing and the challenge injection were given intraperitoneally. The ribosomal vaccine protected mice as early as 1 day after vaccination, and the protection lasted at least 6 days. LPS-specific antibodies were detectable 6 but not 2 days after vaccination. The ribosomal vaccine protected mice also against a heterologous serotype of Pseudomonas. Injection of purified LPS did not protect mice earlier than at day 3, and the protection induced by LPS was serotype specific. Ribonucleic acid (RNA) isolated from the ribosomal vaccine had the same protective properties as the ribosomes. RNA induced serotype-nonspecific protection as quickly as 1 day after injection, and the protection lasted at least 6 days. However, the capacity to induce antibodies to LPS was lost or reduced. It is concluded that the serotype-nonspecific protection induced by RNA and the serotype-specific protection induced by LPS are due to different mechanisms. Experiments with combined vaccines containing RNA and LPS demonstrated that the addition of RNA to LPS resulted in a slight increase in LPS-specific antibodies. The data presented indicate that both the serotype-specific protection induced by LPS and the serotype-nonspecific protection induced by RNA contribute to the protective activity of the ribosomal vaccine.