Identification of novel agents to eradicate the residual lens cell population following cataract surgery provides one mode of preventing PCO formation. The present study investigated the biological mechanism of As(2)O(3) cytotoxicity in a human lens cell line and capsular bag system. FHL 124 cell survival was assessed by quantification of total protein content, a cell population measure. Gene changes were detected by Real-time PCR; apoptosis by TUNEL assays. Intracellular calcium was measured by real-time fluorimetric single-cell digital imaging techniques after Fura-2 incorporation. In vitro human capsular bags were generated from donor eyes, which involved sham cataract surgery then use of the Perfect Capsule device to form a closed system to deliver As(2)O(3) for 2min. On-going observations were by phase-contrast microscopy. Cellular architecture was examined by fluorescence immunocytochemistry. FHL 124 cells demonstrated a dose-dependent sensitivity to As(2)O(3) exposure. A 2min exposure of As(2)O(3) to cells within the capsular bag, using the perfect capsule system, resulted in total cell death when used at 100mM. As(2)O(3) provoked an ER stress response identified through an upregulation of known genes. As(2)O(3) depleted the calcium store and consequently lead to reduced calcium signalling. As(2)O(3) increased rates of apoptosis. Arsenic trioxide provokes ER stress that leads to down-regulation of calcium signalling resulting in apoptosis. The application of As(2)O(3) to cells within the capsular bag for a 2min window using the Perfect Capsule system predicts putative therapeutic benefit in vivo.