Rabbits with sterile, right ventricular cardiac vegetationss were challenged with Staphylococcus aureus and serum-susceptible or -resistant isolates of Pseudomonas aeruginosa. None of the rabbits challenged with serum-susceptible P. aeruginosa died or had greater than 10(2) colony-forming units (cfu)/g cultured from vegetations two weeks later. In contrast, 78% of animals challenged with serum-resistant P. aeruginosa died within three weeks, and 74% sacrificed at three days had organisms cultured from vegetations. All of the animals challenged with S. aureus died, and all had greater than 10(8) cfu of P. aeruginosa/g in vegetation tissue at three days. There was a significantly greater number of organisms (P less than 0.001) in the vegetations of animals dying of S. aureus infection than in those of animals with P. aeruginosa endocarditis (mean, 10(9.6) vs. 10(7.5) cfu/g, respectively). Left-sided endocarditis was produced in 100% of rabbits injected with serum-resistant P. aeruginosa. These models could be used for studies of the pathogenesis and therapy of P. aeruginosa endocarditis.