Direct gastric mucosal cell damage mediated by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. We recently suggested that this direct cytotoxicity of NSAIDs is caused by their membrane-permeabilization activity. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, can protect gastric mucosa against lesion formation mediated by NSAIDs. However, the mechanism by which this occurs is not fully understood. In this study, we show that GGA acts to stabilize membranes against NSAIDs. GGA suppressed NSAID-induced permeabilization of calcein-loaded liposomes and NSAID-induced stimulation of K(+)-efflux across the cytoplasmic membrane in cells. GGA was effective even when coadministered with NSAIDs and was also able to restore membrane fluidity that had been compromised by NSAIDs. This mechanism seems to play an important role in the antiulcer activity of GGA.