Trivalent forms of arsenic are medically used (e.g. leukaemia, leishmaniosis, trypanosomiasis), thus, arsenic contamination of air, water, food is associated with several neurological, cardiovascular, hematological illnesses and cancers. The mechanisms of arsenic interaction with cell systems are not fully clear. In our study we propose that disturbances in calcium homeostasis could be an important mechanism in arsenic induced cytotoxicity. We studied two human cell models: neuroblastoma (SY5Y) and embryonic kidney (HEK 293) cells using confocal microscopy with calcium sensitive dyes fluo4/AM and rhod2/AM. For evaluation of cytotoxicity a trypan blue and a Hoechst staining were used. As₂O₃ raised significantly (t-test: p<0.05) [Ca²⁺]_i, even when no Ca²⁺ was added to the external solution (170±4.84% vs. 164±2.93% in neuroblastoma and 166±1.68% vs. 241±1.68% in HEK cells). Steady state increase of [Ca²⁺]_i and calcium-spikes were observed using an external solution containing 2mM calcium as well as with an external solution with contained nominal no calcium. The increase of [Ca²⁺]_i was not reversible. Staining of the internal calcium stores with rhod 2 revealed that calcium is released from the internal calcium stores. The cytotoxicity tests show that a incubation of 24, 48 and 72h with 1 mM As ₂O₃ significantly (t-test, p<0.05) reduced cell viability (CV) and increased DNA damage of SY5Y and HEK 293 cells.