Hepatocellular carcinoma (HCC), or liver cancer, is one of the fastest growing cancers in the United States. Current liver ablation methods are thermal based and share limitations resulting from the heat sink effect of blood flow through the highly vascular liver. In this study, we explore the feasibility of using histotripsy for non-invasive liver ablation in the treatment of liver cancer. Histotripsy is a non-thermal ablation method that fractionates soft tissue through the control of acoustic cavitation. Twelve histotripsy lesions ∼1 cm(3) were created in the livers of six pigs through an intact abdomen and chest in vivo. Histotripsy pulses of 10 cycles, 500-Hz pulse repetition frequency (PRF), and 14- to 17-MPa estimated in situ peak negative pressure were applied to the liver using a 1-MHz therapy transducer. Treatments were performed through 4-6 cm of overlying tissue, with 30%-50% of the ultrasound pathway covered by the rib cage. Complete fractionation of liver parenchyma was observed, with sharp boundaries after 16.7-min treatments. In addition, two larger volumes of 18 and 60 cm(3) were generated within 60 min in two additional pigs. As major vessels and gallbladder have higher mechanical strength and are more resistant to histotripsy, these remained intact while the liver surrounding these structures was completely fractionated. This work shows that histotripsy is capable of non-invasively fractionating liver tissue while preserving critical anatomic structures within the liver. Results suggest histotripsy has potential for the non-invasive ablation of liver tumors.