Objective To investigate the safety and efficacy of real-time ultrasound guidance and ultrasound-assisted guidance in percutaneous liver parenchymal biopsy. Methods A retrospective analysis was conducted based on patient information spanning from January 2016 to January 2021, pertaining to liver biopsy procedures performed at our hospital. The technique success rate, sample adequacy rate, specimen length, number of specimens, number of portal tracts, and occurrence of complications were recorded. Results This study involved 1219 patients. No significant differences were found in technique success rate, sample adequacy rate, specimen length, number of specimens or number of portal tracts. The rate of post-biopsy complications was significantly lower for real-time ultrasound-guided liver parenchymal biopsy (6.18%) compared to ultrasound-d guidance (14.66%), with a statistically significant difference (P<0.001).Conclusion Both real-time ultrasound and ultrasound-assisted techniques proved effective in obtaining liver specimens. However, when compared to ultrasound-assisted guidance, real-time ultrasound-guided liver biopsy exhibited a reduced incidence of complications and offered improved safety.