A 14 year retrospective study of perigraft seroma, defined as an enlarging sterile fluid collection at the site of a prosthetic graft, revealed well-documented cases in 5 of 118 extraanatomical bypasses (4.2 percent), 3 of 248 aortic reconstructive procedures (1.2 percent), and 1 of 395 femoropopliteal bypasses (0.3 percent). These nine cases involved four polytetrafluoroethylene and five Dacron grafts. There were five graft thromboses, one instance of limb loss, two graft infections, two deaths, and 13 separate surgical procedures related to the perigraft seroma. Histologic studies revealed a fibrous pseudomembrane lining the perigraft seroma wall and immature fibroblasts lining the graft. Sera from three patients with perigraft seroma, five patients with well-incorporated prosthetic grafts, and three healthy volunteer subjects were tested for in vitro evidence of fibroblast inhibition against fibroblast tissue cultures derived from the pseudomembrane of a perigraft seroma. Control fetal calf serum, sera from all three healthy subjects, and sera from all five patients with well-incorporated grafts allowed fibroblast proliferation. In contrast, sera from all three patients with perigraft seroma inhibited fibroblast growth. Furthermore, sera collected 1, 2, and 3 months after graft removal from one patient and serum collected 3 months after spontaneous resolution of a perigraft seroma from another patient failed to inhibit fibroblasts. We have concluded that patients with perigraft seroma have a high rate of graft and limb loss and require multiple reoperations. The pathogenesis of perigraft seroma appears to involve a humoral fibroblast inhibitor which prevents maturation and proliferation of perigraft fibroblasts, leading to poor graft incorporation. The decrease of inhibition below detectable levels after graft removal or spontaneous resolution of the perigraft seroma suggests that the graft may induce host production of the inhibitor. Effective therapy of perigraft seroma may include fibroblast modulation, removal of the inciting graft, or both.