A mouse model was developed to study the natural history of vascular prosthetic graft infection due to Staphylococcus epidermidis. Graft infections were established in the back subcutaneous tissue of 46 mice by implantation of Dacron prostheses colonized in vitro with slime-producing S. epidermidis to form an adherent bacterial biofilm [1.7 x 10(7) colony forming units (CFU)/cm2 graft]. Control animals (n = 16) had implantation of sterile Dacron prostheses. None of the control animals developed a graft infection or graft-cutaneous sinus tract. All study animals developed a biofilm graft infection with typical anatomic (perigraft abscess), microbiologic (low bacterial concentration in surface biofilm), and immunologic (normal white blood count) characteristics. A graft-cutaneous sinus tract developed in a significantly higher number of mice with infected grafts by 8-10 weeks (9 of 21) compared to infected grafts explanted at 2 and 4-6 weeks (1 of 25, P < 0.01) and controls (0 of 16, P < 0.03). By 8-10 weeks, 2 animals had no signs of graft infection and the S. epidermidis study strain was not recoverable from 7 grafts. The natural history of bacterial biofilm vascular prostheses infection in the mouse model was similar to that in man, provoking a chronic inflammatory process curiously presenting as a perigraft abscess or graft-cutaneous sinus tract.