The interactions of arsenic derived compounds with cell systems are not fully elucidated; yet, As2O3 is used in humans to treat some forms of cancers. We have previously proposed that modulation of calcium homeostasis induced by As2O3 could be an important mechanism in induced cytotoxicity. Using human cell models (neuroblastoma, embryonic kidney cells-HEK) and confocal microscopy with calcium sensitive dye fluo 4-AM we found that As2O3 is able to modulate calcium signalling even with a low concentration of 100pM. The rise of calcium was not reversible with As2O3. Steady state increase of [Ca2+ ]i and calcium-spikes were observed. Calcium rise was time and drug concentration dependent. The calcium rise in neuroblastoma cells was: 1mM: 171±5%, 100nM: 232±3.2%, 10nM: 189±4%, 1nM. 177±1.7%, 100pM: 122±0.46% and in HEK 1mM: 167±1.68%, 100nM: 263±2% 10nM: 232±1.4%, 1nM: 197±2.2%, 100pM:153±4.3%. At these low environmental and clinical relevant concentrations of As2O3 occurrence of apoptosis and DNA damage was shown by staining with Hoechst 33347. Our results suggest that low concentrations of As2O3 are able to interfere with physiological processes in diverse cell models.