Highly efficient removal of bilirubin from blood by hemoperfusion for liver failure therapy remains a challenge in the clinical field due to the low adsorption capacity and slow adsorption kinetics of currently used bilirubin adsorbents (e.g., activated carbon and ion-exchange resin). Recently, porous aromatic frameworks (PAFs) with high surface areas, tunable structures, and remarkable stability provide numerous possibilities to obtain satisfying adsorbents. Here, a cationic PAF with more mesopores, named iPAF-6, is successfully constructed via a de novo synthetic strategy for bilirubin removal. The prepared iPAF-6 exhibits a record-high adsorption capacity of 1249 mg g −1 and can adsorb bilirubin from 150 mg L −1 to normal concentration in just 5 min. Moreover, iPAF-6 shows a removal efficiency of 96% toward bilirubin in the presence of 50 g L −1 bovine serum albumin. It is demonstrated that positively charged aromatic frameworks and large pore size make a significant contribution to its excellent adsorption ability. More notably, iPAF-6/polyethersulfone composite fibers or beads are fabricated for practical hemoperfusion adsorption, which also show better removal performance than commercial adsorbents. This work can offer a new possibility for designing PAF-based bilirubin adsorbents with an appealing application prospect. Bilirubin is the major product of hemoglobin metabolism and is transported by albumin to liver for excretion. [1] The normal total bilirubin level in serum is 0.1−1.0 mg dL −1. [2] However, people with liver failure cannot eliminate bilirubin timely, leading to the excess accumulation of bilirubin in blood, called hyperbilirubinemia. [3] The extra bilirubin can cause yellow discoloration of skin and also bring about series of injuries to tissues and organs, and even result in death. [4] Therefore,