Arsenic compounds are classic example as toxics and carcinogens that occur in the environment (especially drinking water) which are of a great danger for the human's health. Paradoxically, some arsenic species e.g. arsenic trioxide (As₂O₃), are clinically used in humans to treat some forms of cancer (e.g. leukemia). We have previously demonstrated that As₂O₃ acts in tumour and non-tumour cell models by releasing calcium from the internal calcium stores inducing cell type specific cytotoxicity. Since calcium homeostasis is important for physiological and pathological function of cells we have further investigated the involvement of internal calcium stores of neuroblastoma and HEK cells. Calcium level was analysed using laser scanning microscopy and specific calcium stores blokers/releasers: caffeine, to release the calcium from the internal calcium stores before application and in co-application with As₂O_3; cyclosporine A, a mitochondrial pore inhibitor; ryanodine, to inhibit the ryanodine sensitive calcium release. The application of caffeine, cyclosporine A and ryanodine alone did induce a slight [Ca²⁺]_i rise in neuroblastoma and HEK cells. In HEK cells, the [Ca²⁺]_i rise induced by cyclosporine A and ryanodine was higher than in neuroblastoma cells, probably because these substances have secondary effects, interfering with other physiological processes. In neuroblastoma cells, co-application of caffeine, cyclosporine A or ryanodine with As₂O₃did reduce the calcium rise as induced by As₂O₃ alone. This could mean that As₂O₃ inducedsignals are positively modulated by RyR, ER and mitochondria. Interestingly, in HEK cells different effects were observed compared to neuroblastoma cells. The co-application of As₂O₃ with caffeine and respectively ryanodine slightly increased calcium rise comparing with [Ca²⁺]_i elevation induced by As₂O₃ alone, a fact that could underline that RyR and ER regulates in the negative way the As₂O₃ induced [Ca²⁺]_i elevation. Thus, cyclosporine A did reduce the As₂O₃ induced [Ca²⁺]_i rise probably since mitochondrial calcium release is positively modulated by As₂O₃. We conclude that As₂O₃ specifically modulates the calcium stores of cells which could be one reason of the cell type specific effects observed in cytotoxicity tests.