In ?I integrins, including leukocyte function-associated antigen 1 (LFA-1), ligand-binding function is delegated to the ?I domain, requiring extra steps in the relay of signals that activate ligand binding and coordinate it with cytoplasmic signals. Crystal structures reveal great variation in orientation between the ?I domain and the remainder of the integrin head. Here, we investigated the mechanisms involved in signal relay to the ?I domain, including whether binding of the ligand intercellular adhesion molecule-1 (ICAM-1) to the ?I domain is linked to headpiece opening and engenders a preferred ?I domain orientation. Using small-angle X-ray scattering and negative-stain EM, we define structures of ICAM-1, LFA-1, and their complex, and the effect of activation by Mn2+ Headpiece opening was substantially stabilized by substitution of Mg2+ with Mn2+ and became complete upon ICAM-1 addition. These agents stabilized ?I-headpiece orientation, resulting in a well-defined orientation of ICAM-1 such that its tandem Ig-like domains pointed in the opposite direction from the ?-subunit leg of LFA-1. Mutations in the integrin ?I domain ?1/?1' helix stabilizing either the open or the closed ?I-domain conformation indicated that ?1/?1' helix movements are linked to ICAM-1 binding by the ?I domain and to the extended-open conformation of the ectodomain. The LFA-1-ICAM-1 orientation described here with ICAM-1 pointing anti-parallel to the LFA-1 ?-subunit leg is the same orientation that would be stabilized by tensile force transmitted between the ligand and the actin cytoskeleton and is consistent with the cytoskeletal force model of integrin activation.