New indocyanine green (IR820) is an indocyanine green analog which has attracted increasing attention in cancer phototherapy for the prominent absorbance at near-infrared region and improved stability. However, the lack of tumor targeting ability is still an obstacle that severely limits the application of IR820. Lactobionic acid (LA) is a ligand for the asialoglycoprotein receptors which are overexpressed on the membrane of hepatocellular carcinoma cells. In this work, three conjugates of LA and IR-820, namely LA-IR820, LA-SS-IR820, and LA-DEG-IR820, were developed for targeted photodynamic therapy of hepatocellular carcinoma (HCC). The in vitro photodynamic effect study shows that LA-IR820, LA-SS-IR820 and LA-DEG-IR820 exhibit similar singlet oxygen quantum yield as compared to free IR820. The cellular uptake study demonstrates that LA-IR820, LA-SS-IR820, and LA-DEG-IR820 exhibit enhanced cellular uptake amount as compared to free IR820 due to the ligand-receptor interactions between LA and asialoglycoprotein receptor overexpressed on the membrane of HepG2 cells. Among these three conjugates, LA-IR820 with hydrodynamic diameter of 154.6 ± 6.1 nm exhibits the highest cellular uptake amount. The cellular reactive oxygen species (ROS) generation study shows that LA-IR820, LA-SS-IR820 and LA-DEG-IR820 display enhanced cellular ROS level as compared to free IR820 and LA-IR820 exhibits the highest cellular ROS level upon 600 mW/cm 2 660 nm laser irradiation. As a result, LA-IR820, LA-SS-IR820 and LA-DEG-IR820 exhibit enhanced photocytotoxicity against HepG2 cells as compared to free IR820 and LA-IR820 exhibits the highest photocytotoxicity. LA-IR820, LA-SS-IR820, and LA-DEG-IR820 show significant potential for the targeted photodynamic therapy of HCC.