Murine models of autoimmunity allow the study of the earliest events in disease pathogenesis. Our laboratory has developed a xenobiotic induced model of primary biliary cirrhosis (PBC) following immunization of mice with 2‐octynoic acid coupled to bovine serum albumin (2‐OA‐BSA), an antigen selected following quantitative structure‐activity relationship analysis of the E2 subunit of the pyruvate dehydrogenase complex (PDC‐E2), the immunodominant autoantigen of PBC. Recent data in humans with PBC has suggested that a major component of liver pathology is due to activation of innate immunity. We took advantage of our 2‐OA‐BSA model and immunized mice with and without the addition of α‐galactosylceramide (α‐GalCer), an invariant natural killer T cell activator. Importantly, we report herein that 2‐OA‐BSA‐immunized mice exposed to α‐GalCer develop a profound exacerbation of their autoimmune cholangitis, including significant increases in CD8⁺ T‐cell infiltrates, portal inflammation, granuloma formation, and bile duct damage. Furthermore, such mice produce increased levels of antimitochondrial antibodies and have evidence of fibrosis, a feature not previously reported in the murine models of PBC. Conclusion: Our data suggests a primary role of innate immunity in the exacerbation of autoimmune cholangitis and also become a logical explanation for the recurrence of PBC following liver transplantation in the absence of major histocompatability complex compatibility. We submit that PBC begins with loss of tolerance to PDC‐E2 and a multilineage antimitochondrial response in which autoreactive CD8⁺ T cells are critical. However, the perpetuation of disease and its exacerbation will also be modulated by innate immune mechanisms. (HEPATOLOGY 2011;)