Tissue macrophages have an important role in the maintenance of liver homeostasis, and their functions are closely related to spatial localization. Here, through integration of whole liver lobe imaging and single-cell RNA sequencing analysis of CX3CR1 cells in the mouse liver, we identified a dense network of CX3CR1CD63 liver portal area macrophages (LPAMs) that exhibited transcriptional and spatial differences compared with CX3CR1CD207 liver capsular macrophages. The survival of LPAMs was dependent on colony-stimulating factor 1 receptor (CSF1R). LPAMs colonized the hepatic portal area of mice after birth and were replenished from bone-marrow-derived cells during liver homeostasis. LPAMs efficiently captured antigens derived from hepatocytes and closely interacted with sympathetic nerves around the portal vein. Deletion of LPAMs led to increased neutrophil infiltration and worsened sympathetic nerve degeneration during hepatic nonalcoholic steatohepatitis. In summary, our results provide insights into a distinct subset of nerve-associated portal macrophages that function to maintain liver immune homeostasis.