Intercellular adhesion molecules (ICAMs) are cell surface proteins that play a crucial role in the body’s immune response and inflammatory processes. ICAM1 and ICAM2 are two ICAM family members expressed on the surface of various cell types, including endothelial cells. They mediate the interaction between immune cells and endothelial cells, which are critical for the trafficking of leukocytes across the blood vessel wall during inflammation. Although ICAM1 plays a prominent role in the leukocyte extravasation cascade, it is less clear if ICAM2 strengthens ICAM1 function or has a separate function in the cascade. With CRISPR–)Cas9 technology, endothelial cells were depleted for ICAM1,ICAM2, or both, and we found that neutrophils favored ICAM1 over ICAM2 to adhere to. However, the absence of only ICAM2 resulted in neutrophils that were unable to find the transmigration hotspot, i.e. the preferred exit site. Moreover, we found that ICAM2 deficiency prevented neutrophils to migrate against the flow. Due to this deficiency, we concluded that ICAM2 helps neutrophils find the preferred exit sites and thereby contributes to efficient leukocyte extravasation.