IClswell is the chloride current induced by cell swelling, and plays a fundamental role in several biological processes, including the regulatory volume decrease (RVD). ICln is a highly conserved, ubiquitously expressed and multifunctional protein involved in the activation of IClswell. In platelets, ICln binds to the intracellular domain of the integrin αIIb chain, however, whether the ICln/integrin interaction plays a role in RVD is not known. Here we show that a direct molecular interaction between ICln and the integrin α-chain is not restricted to platelets and involves highly conserved amino acid motifs. Integrin α recruits ICln to the plasma membrane, thereby facilitating the activation of IClswell during hypotonicity. Perturbation of the ICln/integrin interaction prevents the transposition of ICln towards the cell surface and, in parallel, impedes the activation of IClswell. We suggest that the ICln/integrin interaction interface may represent a new molecular target enabling specific IClswell suppression in pathological conditions when this current is deregulated or plays a detrimental role.