The virulence of Wolinella recta isolates was studied in an experimental animal model by using monoinfection of BALB/c mice. Infection with clinical isolates of W. recta 576 and W. recta 234 induced dry, flat, depressed gangrenous necrotic skin lesions, whereas W. recta ATCC 33238 failed to induce a similar lesion. Histological examination of the skin lesion 72 h postinfection revealed coagulation necrosis of the epidermis, subcutis and cutaneous truncus muscle, with marked exudation of serum proteins and neutrophils. Virulence-modulating agents such as dexamethasone, galactosamine, hydrazine sulfate, and dextran microcarrier beads were used in conjunction with W. recta infection. Dexamethasone, hydrazine sulfate, and dextran beads enhanced the infectivity and pathogenicity of W. recta for lesion formation and tissue destruction compared with what was found in untreated control mice. Galactosamine sensitization enhanced the virulence potential of W. recta to such an extent that a lethal outcome was observed. Laboratory passage of clinical isolates demonstrated a decreased virulence in high-passage strains, which correlated with the minimal virulence observed in the extensively passaged W. recta ATCC 33238. Serum immunoglobulin G (IgG) and IgM responses were detected in the serum of infected animals, and cross-reacting antibody indicated variation in the antigenic makeup of various W. recta strains. Enhanced IgG antibody responses were observed following the secondary challenge. Mice with acquired antibody response to initial infection remained susceptible to lesion formation with subsequent challenge, but the size of the lesion was significantly reduced, indicating partial protection. Serum IgG and IgM antibody levels were significantly increased by active immunization when compared with levels in mice which had recovered from infection. The immunization significantly decreased the lesion size; however, even these high levels of antibody failed to abrogate the lesion induction.