Portal branch ligation (PBL) may prevent liver failure after extended hepatic resection. However, clinical studies indicate that tumors within the ligated lobe develop accelerated growth. Although it is well known that tumor growth depends on the host's microvascularization, there is no information on how PBL affects the hepatic microcirculation. Our aims were to determine hepatic artery response, liver microcirculation, tissue oxygenation and cell proliferation after PBL. Therefore, we used intravital multifluorescence microscopy, laser Doppler fluxmetry, immunohistochemistry and biochemical techniques to examine microcirculatory responses, microvascular remodeling and cellular consequences after left lateral PBL in BALB/c mice. During the first 7d PBL induced a reduction of left hilar blood flow by ~50%. This resulted in 80% sinusoidal perfusion failure, significant parenchymal hypoxia and liver atrophy. After 14d, however, left hilar blood flow was found restored. Remodeling of the microvasculature included a rarefaction of the sinusoidal network, however, without substantial perfusion failure, compensated by a hepatic arterial buffer response and significant sinusoidal dilatation. This resulted in normalization of tissue oxygenation, indicating arterialization of the ligated lobe. Interestingly, late microvascular remodeling was associated with increased eNOS expression, significant hepatocellular proliferation and weight gain of the ligated lobe. Thus, PBL induces an only initial microcirculatory failure with liver atrophy, followed by a hepatic arterial buffer response, microvascular remodeling, normoxygenation and hepatocellular proliferation. This may explain the accelerated tumor progression occasionally observed in patients after PBL.