The acute gastroduodenal mucosa injury and gastric potential difference (GPD) drops provoked by 14-day administration of 20 mg/day of a new piroxicam formulation (piroxicam-beta-cyclodextrin), 20 mg/day standard piroxicam and 100 mg/day indomethacin were evaluated and compared in a randomized, double-blind, placebo-controlled study carried out on 64 volunteers. Endoscopic examinations, performed after 14-day treatment, demonstrated that piroxicam-beta-cyclodextrin was less gastrolesive (mean endoscopic score +/- SE = 0.56 +/- 0.2) than either piroxicam (2.06 +/- 0.5) or indomethacin (2.25 +/- 0.5) (p < 0.01). The drop in GPD after a single dose of the assigned drug was considerably greater for piroxicam and indomethacin than for piroxicam-beta-cyclodextrin (p < 0.01), which registered similar values to placebo. Since GPD is an expression of the anatomo-functional integrity of the gastric barrier, the results indicate that piroxicam-beta-cyclodextrin exerts less direct acute damage on the gastric mucosa. Therefore, when administered short-term, piroxicam-beta-cyclodextrin appears to be less gastrolesive than either indomethacin or the standard piroxicam formulation.