Abstract Draining lymph nodes (LNs) are specialized sites where adaptive immune responses take place. Recently, the anatomical location of two LNs draining the mouse liver, named as portal LN (PLN) and celiac LN (CLN) respectively, has been characterized. However, the immune responses in the liver-draining LNs and their contribution to the establishment and maintenance of liver tolerance are still not fully understood. In our further study, we find that these two liver-draining LNs (PLN and CLN) have different lymphatic vessels, excluding the possibility that one LN is secondary to the other one. Interestingly, although both PLN and CLN can drain liver lymph directly, they are different in many aspects. The two liver-draining LNs have different cellular composition, with PLN being highly similar to mesenteric LN but different from periphery LNs, and CLN being special with unique composition of innate immune cells. Importantly, the development of these two liver-draining LNs might be controlled by different transcription factors. Moreover, our preliminary data shows that the immune responses of these two liver-draining LNs exhibit different features during exogenous pathogen infection. Overall, PLN and CLN are two liver-draining LNs with distinct characteristics and their contribution to liver tolerance remains to be defined.