A series of platinum(II) complexes bearing Delta (4)-1,2,4-oxadiazoline ligands have been synthesized and characterized. Their in vitro antitumor activity has been assessed in platinum-sensitive and -resistant human ovarian cancer cell lines (PEO1, PEOCisR, PEOCarboR, and SK-OV3), as well as in colon cancer (SW948) and testicular cancer cell lines (N-TERA). All compounds tested showed potent cytotoxicity in the platinum-sensitive cell lines and retained activity in the cisplatin- and carboplatin-resistant lines, with IC 50 values similar to the parental drug sensitive counterpart. We propose, therefore, that platinum(II) oxadiazoline complexes may possess a novel mechanism of action, which render them active in tumor cells, with resistance to currently used platinum anticancer agents.