TRPM2 is nonselective cation channel that acts as an oxidative stress sensor in cells. A splice variant of TRPM2 (TRPM2-S) modulates TRPM2 activity when coexpressed in HEK293 cells (Zhang et al, 2003). The aim of the present study was to assess the role of TRPM2 in oxidative-stress induced calcium influx and cell death in endogenously expressing cells following exposure to hydrogen peroxide (H₂O₂). Rat insulinoma CRI-G1 cells were seeded into 24-well plates at 50.000 cells per well and incubated at 37 ^oC / 5% CO₂ overnight. Cells were transfected with TRPM2S or vector, and after 48h cell death was assesssed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction assay. A statistically significant reduction (F(1,46)= 9.277, p=0.0038) in oxidative stress-mediated cell death was observed after 18h post-exposure to 100 µM Hin CRI-G1 cells 2^O2 transfected with TRPM2-S (n=12-14 replicates pooled from three different experiments).Primary cultures of striatal neurons were prepared from humanely sacrified E18 Sprague-Dawley rat embryos. Dissociated neurons were transfected and seeded into 96-well plates at 40-60.000 cells per well and incubated at 37 ^oC / 5% CO₂ for 48 h. Fluorimetric imaging of Fluo-3 AM loaded cells was used to determine intracellular free Ca ²⁺ ion concentration changes. Fluorimetric imaging of Sytox Green was used to determine loss of membrane integrity as indicative of cell death. In the presence of TRPM2-S, both Ca ²⁺ influx and cell death following exposure to 1 µM-3 mM HOwere inhibited in a 22 statistically significant manner ( F(1,44)=97.40, p<0.0001; and F(1,38)=158.2, p<0.0001: for Ca ²⁺ influx and cell death, respectively). In summary, we have demonstrated that TRPM2 function contributes to oxidative stress-induced cell death in striatal neurons. Furthermore, our data conclusively demonstrate TRPM2 role on oxidative stress-induced cell death in pancreatic beta cells, as previously suggested by Herson et al (1999) and Hara et al (2002). Thus, TRPM2 plays a key role on calcium homeostasis and regulation of cell death following oxidative stress insult in endogenous expressing systems.