Existing evidence suggests that acidic sphingomyelinase (ASMase) controls hepatic stellate cell activation and may contribute to fibrosis. The objective of this study was to determine if the pharmacologic inhibition of ASMase limits CCl4 induced hepatic fibrosis. C57BL/6 mice were given intraperitoneal injections of CCl4 for 8 weeks to induce fibrosis. Some animals received amitriptyline in their drinking water to inhibit ASMase activity. Liver sections were examined and fibrosis stage (0–4) was scored. Treatment with CCl4 generated significant hepatic fibrosis after week 4 (3.0 ± 0 vs. 1.2 ± 0.3) and week 6 (3.6 ± 0.2 vs. 1.3 ± 0.2) when compared to vehicle. Hepatic cirrhosis (stage 4 fibrosis) was induced after 8 weeks of CCl4 treatment compared to vehicle (3.83 ± 0.41 vs. 0.67 ± 1.0, p<0.05). Inhibition of ASMase caused a significant decrease in hepatic collagen deposition at week 4 (2 ± 0), week 6 (2 ± 0) and week 8 (2.5 ± 0.3) when compared to CCl4 treatment (p<0.05 for each). These data suggest that inhibition of ASMase may be a therapeutic target in hepatic fibrotic disorders and may prevent the progression to cirrhosis.