BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal mucosal damage. Omeprazole prevents the formation, and accelerates the healing, of NSAID-induced ulcers. AIM: To test whether omeprazole accelerates healing of standardized gastroduodenal lesions in the presence of diclofenac. METHODS: In a double-blind, double-dummy, placebo-controlled, crossover study, 12 healthy volunteers received consecutive, 2-week courses of omeprazole (40 mg o.d.) and placebo, in random order, with an intervening, 4-week washout period; diclofenac (50 mg t.d.s.), was given for the second week of each course. Five endoscopies were performed, one at the outset and the others before and after each course of diclofenac. Biopsies were taken from the endoscopically normal mucosa of the corpus, antrum and duodenum and also from any new mucosal lesion that developed after diclofenac. The sites of biopsies taken before each course of diclofenac were evaluated endoscopically after each course to assess the extent of healing according to a predetermined healing score scale. RESULTS: The healing scores observed after administration of placebo/diclofenac (median=0; range 0-6) and after omeprazole/diclofenac (median=0; range 0-6; P=0.17) did not differ. Small gastroduodenal lesions developed de novo in six subjects during placebo/diclofenac and in seven during omeprazole/diclofenac. Focal chemical gastropathy was observed only in close proximity to macroscopic lesions. CONCLUSIONS: In healthy subjects, omeprazole does not accelerate the healing of pre-existing mucosal lesions or prevent the development of small diclofenac-induced mucosal lesions.