BACKGROUND: In this investigation the effects of tricyclic drugs on cellular respiration were studied using the anaplastic astrocytoma cell line IPSB-18 by use of a Clark-type oxygen electrode which measured changes in cellular respiration rate (oxygen consumption), in a dose-response assay. MATERIALS AND METHODS: The drugs investigated were clomipramine, norclomipramine, amitriptyline and doxepin. In addition, the combined effects of dexamethasone and clomipramine on cellular respiration were investigated. RESULTS: It was established that at lower concentrations (0.14 mM-0.5 mM) amitriptyline was the most potent inhibitor of cellular respiration. Previous studies have indicated that inhibition of cellular respiration is considered an indicator of apoptosis. Overall, it appeared that clomipramine and its metabolite norclomipramine were the most potent inhibitors of cellular respiration in glioma cells over the concentration range 0.5-0.9 mM. Dexamethasone was able to induce inhibition of cellular respiration both alone in glioma cells, and in combination with clomipramine, where it had an additive or synergistic effect, thereby increasing cell death. CONCLUSION: The extensive research currently ongoing and previously reported regarding the use of clomipramine as a potential antineoplastic agent aimed at targeting the mitochondria of gliomas is promising.