Although chronic Pseudomonas aeruginosa infection is the major cause of morbidity and mortality in cystic fibrosis (CF) patients, there is no approved vaccine for human use against P. aeruginosa. The goal of my research was to establish whether a multivalent vaccine containing P. aeruginosa type A and B flagellins as well as the outer membrane proteins OprF and OprI would promote enhanced clearance of P. aeruginosa . To test this I utilized two animal models, mice and 4–6 month old African green monkeys. Intramuscular immunization of mice with flagellins + OprI (separate), or OprI-Flagellins fusion proteins generated significant anti-flagellin IgG responses. However, only OprI-Flagellins fusion generated OprI-specific IgG. Although immunization of young African green monkeys with OprF_311–341-OprI-Flagellins promoted a high level of antigen-specific IgG ten days post-boost, there was significant reduction in IgG three months later. Immunization of mice and young African green monkeys with OprF_311–341-OprI-Flagellins elicited high affinity flagellins, OprI, and OprF-specific antibodies that individually promoted extensive deposition of C3 on P. aeruginosa. Although these antibodies exhibited potent antibody-dependent complement-mediated killing of nonmucoid bacteria, they were significantly less effective with mucoid isolates. Mice immunized with OprF_311–341-OprI-Flagellins had a significantly lower bacterial burden three days post-challenge and cleared the infection at a significantly faster rate than OprF-OprI immunized mice. In addition, mice that were passively immunized with OprF_311–341-OprI-Flagellins monkey immune plasma had significantly less bacteria, inflammation, and lung damage throughout the infection compared to control immunized mice. Based on my results, OprF_311–341-OprI-A- and B-flagellin fusion proteins have substantial potential as a vaccine against nonmucoid P. aeruginosa, which appears to be the phenotype that initially colonizes CF patients.