Background & Aims The biochemical response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) correlates with the long-term prognosis and thus could allow the identification of the patients needing new therapeutic approaches. Due to variation in both endpoints and studied populations, there is still no full agreement on the definition of the biochemical response. The aim of our study was to determine, in a population of patients with only early-stage disease, the best biochemical criteria of response to UDCA allowing to predict the absence of poor outcome, as defined by liver-related death, liver transplantation, complications of cirrhosis, or histological evidence of cirrhosis development. Methods The efficiency of several combinations of serum bilirubin, alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcome was assessed after 1 year of UDCA in 165 patients with early-stage PBC followed up for an average 7 years. The Barcelona, Paris, Rotterdam, and Toronto criteria were also assessed. Results The most accurate discrimination of the patients according to the multiple endpoints was given by the following criteria: ALP and AST ⩽1.5× upper limit of normal, with a normal bilirubin level. Responders and non-responders were equally distributed, while all adverse events were observed in non-responders ( p <0.001). These criteria remained valid when early PBC was defined by both normal bilirubin and albumin concentrations at baseline. Conclusions This study defines the best efficient biochemical response to UDCA that identifies patients with early PBC at very low risk of long-term development of liver failure or cirrhosis.