Mice lacking A(1) adenosine receptors (A(1)AR) were thought to be protected from developing fatty liver; however, the contribution of A(1)AR to hepatic fibrosis has not been explored. Here we found that the expression of A(1)AR was decreased in fibrotic liver induced by chronic carbon tetrachloride (CCl(4)) but increased in that induced by bile duct ligation (BDL). Therefore, we examined whether A(1)AR contributes to hepatic fibrosis in CCl(4) and BDL animal models using A(1)AR knockout mice. Compared with wild-type (WT) mice, hepatic fibrosis resulting from chronic CCl(4) exposure was attenuated in A(1)AR(-/-) mice with markedly decreased collagen deposition and reduced hepatic stellate cell activation, whereas bile duct-ligated A(1)AR(-/-) mice displayed a significant increase in hepatic fibrosis. Hepatocyte damage was reduced in A(1)AR(-/-) mice after a single injection of CCl(4), with down-regulation of CYP2E1 and UCP2 gene expression in livers, which resulted in impaired liver sensitivity to CCl(4). However, BDL caused severe bile infarcts in livers of A(1)AR(-/-) mice, with significantly elevated levels of bile acid compared with those in WT mice. CCl(4) and BDL resulted in different expression patterns of genes involved in fibrogenesis in A(1)AR(-/-) mice. These results indicate that A(1)AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.