Staphylococcus aureus is the most prominent musculoskeletal pathogen of man and animals. The persistent emergence of antibiotic-resistant strains has prompted renewed efforts to develop alternative protocols for the treatment and prevention of staphylococcal disease. These efforts have included attempts to develop an effective staphylococcal vaccine. Among the potential vaccine candidates are a group of surface proteins that act as adhesins by virtue of their ability to bind host proteins present in plasma and in the extracellular matrix. Because of our interest in the treatment and prevention of musculoskeletal infection, we have focused on adhesins that contribute to the colonization of bone and cartilage. Based on reports suggesting that colonization is a conserved characteristic of S. aureus strains that cause osteomyelitis and septic arthritis, we have paid particular attention to the factors that contribute to the ability to bind collagen. To date, only one collagen-binding adhesin (Cna) has been identified, and the gene encoding this adhesin (cna) is not present in most S. aureus strains. The possibility that a rare phenotype is conserved among isolates that cause a particular form of infection suggests a cause-and-effect relationship in which the phenotype contributes to the pathogenesis of the disease. To further evaluate that hypothesis, we attempted to determine whether Cna is the only collagen-binding adhesin produced by S. aureus and whether strains that encode cna share additional characteristics that distinguish them from other S. aureus strains. We also studied whether immunization with Cna induces a protective immune response. Our results confirm that Cna is the primary and probably the only collagen-binding adhesin and that the genetic element encoding cna does not encode any additional virulence factors. These results strongly suggest that the only consistent difference between cna-positive and cna-negative strains is the ability to bind collagen. We also demonstrated that vaccination with a recombinant fragment of Cna can protect animals against septic death and limit the ability to colonize bone.