To evaluate the influence of resveratrol on cellular zinc status, NHPrE cells were treated with 6 levels of resveratrol (0, 0.5, 1, 2.5, 5 and 10 µM) and 4 levels of zinc [0, 4, 16 and 32 µM or zinc-deficient (ZD), zinc-normal (ZN), zinc-adequate (ZA) and zinc supplemented (ZS), respectively]. A progressive reduction in cell growth was observed in cells treated with increasing amount of resveratrol (2.5-10 µM). Strikingly, resveratrol treatment at 5 and 10 µM resulted in a dramatic increase in cellular total zinc concentration, especially in ZS cells. Flow cytometric study indicated that resveratrol (10 µM) treatment induced a G2/M arrest in association with the observed cell growth inhibition. Data from an in vitro experiment using zinquin as an indicator of intracellular free Zn(II) status, demonstrated complex interactions between resveratrol and Zn(II). Fluorescent spectrofluorimetry and fluorescent microscopic analyses revealed that intracellular free labile zinc was progressively elevated from ~2-fold in ZS cells with no resveratrol to multi-fold increases in ZA and ZS cells with 10 µM resveratrol, compared to their corresponding ZN cells. Furthermore, increases in cellular zinc status was associated with elevated levels of reactive oxygen species (ROS) and senescence as evidenced by morphological and histochemical changes in cells treated with 2.5 or 10 µM resveratrol, especially in ZA and ZS cells. Taken together, the interaction between resveratrol and zinc in NHPrE cells increases total cellular zinc and intracellular free labile zinc status followed by ROS production and senescence.