The reaction of platinum(II) [Pt(II)] or palladium(II) [Pd(II)] with 2-acetyl pyridine 4N-ethyl thiosemicarbazone, HAc4Et (1) results in the complexes [Pt(Ac4Et)₂] (2) and [Pd(Ac4Et)₂] (3). In a panel of human tumor cell lines of different origins (breast, colon, and ovary cancers), and containing also cisplatin-refractory/resistant cell lines, the in vitro growth inhibitory effect of 1–3 was compared to that of cisplatin by using the sulforodamine B assay. After a 96-hour continuous treatment, both the thiosemicarbazone HAc4Et and the metal compounds [Pt(Ac4Et)₂] and [Pd(Ac4Et)₂] exhibit very remarkable growth inhibitory activities with mean IC₅₀ values of 0.9 n<i>M</i> (0.22–2.47 n<i>M</i>), 0.7 n<i>M</i> (0.15–2 n<i>M</i>) and 0.5 n<i>M</i> (0.17–1.02 n<i>M</i>), respectively. In contrast, cisplatin shows a markedly lower growth inhibitory potency, the mean IC₅₀ in the panel being 2.8 µ<i>M</i> (0.2–8 µ<i>M</i>). In addition to their major cell growth inhibitory potency, complexes 1–3 are characterized by a growth inhibitory profile different from that of cisplatin, being active towards cisplatin-refractory tumor cell lines. These findings, along with the ability of completely overcoming acquired cisplatin resistance from either multifocal or reduced uptake origin, confirm the antitumor potential of HAc4Et and support the hypothesis that both [Pt(Ac4Et)₂] and [Pd(Ac4Et)₂] complexes can be characterized by cellular pharmacological properties distinctly different from those of cisplatin.