This study assessed the effect of stimulation of CB 2 receptors or CB 1 blockade on fibrosis and apoptosis in rats subjected to bile duct ligation (BDL). It was performed in sham and BDL rats for four weeks. Fibrosis-induced rats received a CB 2 receptor agonist β-caryophyllene, CB 1 receptor antagonist, hemopressin, combination of β-caryophyllene and CB 2 antagonist, AM630 or vehicle daily during the last 2 weeks of the BDL ligation. Transaminases activity, bilirubin levels, hepatic collagen content, hydroxyproline level, Bcl2 positive hepatocytes, and mRNA expression of CB 1 , CB 2 receptors and matrix metalloproteinase-1 (MMP-1) genes were measured in all animals. Bile duct ligated rats showed increased bilirubin levels, elevated transaminases activity, increased hepatic collagen content, and hydroxyproline level, reduced Bcl2 positive hepatocytes and increased expression of the assessed messengers in comparison with sham rats. However, fibrotic rats treated with either β-caryophyllene or hemopressin had reduced hepatic collagen content, improved transaminase activity and reduced bilirubin level, ameliorated CB 1 gene expression, and increased MMP-1 gene expression compared with untreated fibrotic rats. These results were associated with attenuated apoptosis with only β-caryophyllene administration. CB 2 receptor blockade by AM630 prevents the effects of β-caryophyllene on CB 1 receptor and MMP-1 genes expression. This study points out that either stimulation of CB 2 receptors or CB 1 blockade can attenuate hepatic fibrosis in bile duct ligated rats. The mechanisms underlying these incidents may open new avenues for attenuating fibrosis and apoptosis of cholestasis- induced liver diseases.