AbstractMalignant pleural mesothelioma (MPM) cells are characterized by chemoresistance associated with glutathione (GSH) metabolism. Ethacrynic acid (EA) is able to inhibit the detoxifying enzyme glutathione‐S‐transferase (GST), which catalyzes the conjugation between GSH and Pt‐based drugs. With the aim of obtaining active bifunctional drugs, a PtII complex containing two EA moieties as leaving groups, namely cis‐diamminobis(ethacrynato)platinum(II), was synthesized, characterized, and tested on four MPM cell lines. The resulting antiproliferative activity was compared with that elicited by the analogue PtIV complex, cis,cis,trans‐diamminodichloridobis(ethacrynato)platinum(IV) (ethacraplatin) and by the co‐administration of free EA and cisplatin. The PtII and PtIV bifunctional complexes showed poorer performance than the reference drug cisplatin alone or in combination with EA. After treatment, cellular GST activity remained consistently unchanged, while the GSH level increased.