Helicobacter pylori infection can be associated with chronic gastric inflammation and hypochlorhydria with increased levels of the proinflammatory cytokines. The current study investigated the effects of TNF-α on programmed death of gastric parietal cells. TNF-α induced apoptosis of parietal cells in isolated perfused rat stomachs at 10ng/mL. In isolated and highly enriched rat parietal cells, 10ng/mL TNF-α induced a 2.6-fold increase in the apoptotic rate. The 55kDa protein of TNFR-1 but not the 75kDa of TNFR-2 was detected by Western blot analysis. TNF-α-induced apoptosis of isolated parietal cells was inhibited by pretreatment with different NF-κB-inhibitors, nitric oxide synthase inhibitors and with antisense-oligodeoxynucleotides against the p65 subunit of NF-κB. Investigation of downstream signaling pathways of apoptosis revealed that TNF-α induced the expression of iNOS, but failed to stimulate the activity of caspase 3. The TNF-α effect on gastric parietal cells may contribute to the atrophy and hypochlorhydria of the gastric mucosa observed during chronic H. pylori infection.