The natural history of PBC is characterized by slowly progressive cholestasis with liver damage, development of cirrhosis and its complications, and death, unless the patient undergoes liver transplantation. The disease has at least three clinical presentations, each with a different course and prognosis: the silent and usually less aggressive form, the asymptomatic form, and the symptomatic form. There are no identifiable features that distinguish the asymptomatic population who will remain symptom-free from those patients who will develop symptoms. As expected, the survival is longer in asymptomatic than in symptomatic patients. Overall survival of asymptomatic PBC is shorter than for an age- and gender-matched control population, but the patients remaining asymptomatic had a survival equal to that of the general population. Natural history studies have identified several variables associated with survival, particularly age, bilirubin, albumin, prothrombin time, ascites, encephalopathy, and advanced histological stage. Development of esophageal varices and hepatocellular carcinoma can also affect survival. Serum bilirubin level is, however, the most heavily weighted prognostic variable and can be used as a simplistic prognostic index for patients with PBC. In the last two decades, natural history models have been developed that include clinical, biochemical, and histological variables, the most popular being the Mayo model. It has the advantage ofavoiding histological variables, and therefore can be applicable to a broad spectrum of patients with PBC. The models may also be used to evaluate the efficacy of different new treatments. Prognostic models based on serial measurements of the independent predictors of poor prognosis would lead to a more accurate prediction of survival; however, they probably will not replace clinical outlook.