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Piano-stool iridium complexes based on the pentamethylcyclopentadienyl ligand (Cp*) have been intensively investigated as anticancer drug candidates and hold much promise in this setting. A systematic study aimed at outlining the effect of Cp* mono-derivatization on the antiproliferative activity is presented here. Thus, the dinuclear complexes [Ir(η⁵-C₅Me₄R)Cl(μ-Cl)]₂ (R = Me, <b>1a</b>; R = H, <b>1b</b>; R = Pr, <b>1c</b>; R = 4-C₆H₄F, <b>1d</b>; R = 4-C₆H₄OH, <b>1e</b>), their 2-phenylpyridyl mononuclear derivatives [Ir(η⁵-C₅Me₄R)(k<i>_N</i>,k<i>_C</i>PhPy)Cl] (<b>2a–d</b>), and the dimethylsulfoxide complex [Ir{η⁵-C₅Me₄(4-C₆H₄OH)}Cl₂(κ<i>_S</i>-Me₂S=O)] (<b>3</b>) were synthesized, structurally characterized, and assessed for their cytotoxicity towards a panel of six human and rodent cancer cell lines (mouse melanoma, B16; rat glioma, C6; breast adenocarcinoma, MCF-7; colorectal carcinoma, SW620 and HCT116; ovarian carcinoma, A2780) and one primary, human fetal lung fibroblast cell line (MRC5). Complexes <b>2b</b> (R = H) and <b>2d</b> (4-C₆H₄F) emerged as the most active ones and were selected for further investigation. They did not affect the viability of primary mouse peritoneal cells, and their tumoricidal action arises from the combined influence on cellular proliferation, apoptosis and senescence. The latter is triggered by mitochondrial failure and production of reactive oxygen and nitrogen species.