Cyclopalladated compounds derived from N,N-dimethyl-1-phenethylamine (dmpa)biphosphine-1,2-bis-(diphenylphosphine)ethanebis(dppe) are described in the literature as promising agents to cancer therapy. It is well known that mitochondria also to be involved in trigger and/or regulation of apoptosis through the mitochondrial permeability transition with release of pro-apoptotic proteins to cytosol. Since cyclopalladated-induced apoptosis in tumoral cells seems to involve respiratory collapses, in this work, we investigated the effects of four cyclopalladated compounds [R(+)Cl dmpa:dppe(1:1); R(+)Cl dmpa:dppe (1:2); S(-)Cl dmpa:dppe (1:1) and S(-)Cl dmpa:dppe (1:2)] on the mitochondrial bioenergetics and oxidative state, using as model isolated rat liver mitochondria. The evaluated parameters were oxygen consumption, mitochondrial swelling, amount of reduced protein thiol groups and lipid peroxidation. At very low concentrations (bellow 5 mM) in the presence of 10 mM Ca²⁺, cyclopalladated compounds are able to induce a mitochondrial swelling suggesting the induction of the mitochondrial permeability transition process. However, this effect was also observed in the absence of Ca²⁺ (presence of EGTA) and classical PTP inhibitors such as cyclosporin A and trifluoperazine did not inhibit it that indicates the occurrence of an unspecific mitochondrial permeability transition process. In parallel, it was observed increase of state 4 rate of respiration and the decrease of transmembrane potential induced by the drugs. Pre-incubation of mitochondria with 0.5 mM dithiothreitol, a potent reducer of thiol groups prevented all these described effects. Indeed, the analysis of mitochondrial protein thiol groups reveals a significant decrease of these reduced groups in the presence of the drugs without induce lipid peroxidation, suggesting that the primary effects of cyclopalladated drugs in isolated mitochondria is caused by modification of thiol groups without involvement of free radicals. Our results indicate that ciclopalladated compounds act as potent thiol modifiers inducing mitochondrial dysfunction related to the pro-apoptotic action of the antitumoral cyclopalladated compounds. Supported by FAPESP, CNPq and FAEP-UMC.