CD147 is known as tumor and regulatory T cell marker and as regulator of chemotaxis, stress response or immune cell function; however, the mode of action of CD147 remains incompletely understood. Using affinity purification mass spectrometry (AP-MS) of HA-tagged CD147 swap and deletion mutants, we examined the CD147 microenvironment. We found previously published interaction partners of CD147 and also identified two highly significant new ones: the plasma membrane calcium ATPase 4 (PMCA4) and moesin. The use of CD147 mutants allowed determining of the respective CD147 parts essential for interaction. Finally, we performed AP-MS of endogenous CD147 from primary human CD4+ T cells and again found CD147 associated with PMCA4.