Chondrocyte apoptosis contributes to the disruption of cartilage integrity in osteoarthritis (OA). Recently, we reported that activation of volume-sensitive Cl- current (I-Cl,I-vol) mediates cell shrinkage, triggering apoptosis in rabbit articular chondrocytes. A cyclooxygenase (COX) blocker is frequently used for the treatment of OA. In the present study, we examined in vitro effects of selective blockers of COX on the TNF-induced activation of I-Cl,I-vol in rabbit chondrocytes using the patch-clamp technique. Exposure of isolated chondrocytes to TNF resulted in an obvious increase in membrane Cl- conductance. The TNF-evoked Cl- current exhibited electrophysiological and pharmacological properties similar to those of I-Cl,I-vol. Pretreatment of cells with selective COX-2 blocker etodolac markedly inhibited I-Cl,I-vol activation by TNF as well as subsequent apoptotic events such as apoptotic cell volume decrease (AVD) and elevation of caspase-3/7 activity. In contrast, a COX-1 blocker had no effect on the decrease in cell volume or the increase in caspase-3/7 activity induced by TNF. Thus, the COX-2-selective blocker had an inhibitory effect on TNF-induced apoptotic events, which suggests that this drug would have efficacy for the treatment of OA.