Potassium channels play an important role in the physiology of the immune system. Lymphocytes and macrophages are involved in the immune response. The voltage-gated potassium channel Kv1.3 is present in T-lymphocytes and takes part in physiological processes such as proliferation and activation. Macrophages are related to the activation of T cells by cytokine production and antigen presentation. Unlike T lymphocytes, macrophages express Kv1.3 and Kv1.5. These two channels can form functional heterotetramers. The presence of Kv1.5 leads to important changes in biophysical, pharmacological and functional properties. A higher Kv1.3/Kv1.5 ratio entails a shift of the half-activation voltage to more hyperpolarized values, changes of the inactivation and a decrease of the IC50 for Margatoxin, a specific blocker of Kv1.3 that has no effects on Kv1.5. We described that mononuclear phagocytes such as bone marrow derived macrophages (BMDM) and Raw 264.7 cells express different Kv1.3/Kv1.5 heterotetrameric compositions. While BMDM present a higher amount of Kv1.3, Raw cells predominantly have Kv1.5. Different responses in both activation and proliferation can be observed. Moreover, the Kv1.3/Kv1.5 ratio can be modified upon the way of activation or immunosuppression. During activation, macrophages increase the expression of Kv1.3 in the functional heterotetramers. Contrarily, immunosuppressive agents caused a decrease in the Kv1.3/Kv1.5 ratio. Different oligomeric compositions led to the corresponding changes in the biophysical, pharmacological and functional properties. The heterotetrameric stoichiometry of the Kv1.3-Kv1.5 complex plays a pivotal role in the regulation of the different responses of the immune system. Supported by BFU2005-00695(Ministerio de Educación y Ciencia, Spain).