The effect of exogenous synthetic prostaglandins and the inhibition of endogenous prostaglandin synthesis on gastrointestinal tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] was studied in female Wistar rats (100 g). Animals were divided into 6 groups: Group I was treated with MNNG alone (No. = 43); group II was treated with MNNG after application of the cyclo-oxygenase inhibitor flurbiprofen (No. = 44); group III was treated with MNNG after oral administration of 16,16-dimethyl-prostaglandin E2 (16,16-dm-PGE2; No. = 43); group IV received flurbiprofen alone (No. = 15); group V was treated with 16,16-dm-PGE2 alone (No. = 11). Animals in group VI served as controls (No. = 15). All drugs were administered orally. Hyperkeratosis and hyperplasia of the forestomach developed by 10 days after the first treatment with the carcinogen. Later, benign papillomas and dysplastic lesions were noted. Progressive ingrowth of squamous epithelium from the forestomach ridge into the glandular stomach started as early as day 13 and was more frequent in animals treated with a combination of MNNG plus flurbiprofen (P less than .001). The first squamous cell carcinomas of the forestomach were detected on day 51. Their incidence was 38, 60, and 42% in groups I, II, and III, respectively. This difference was not statistically significant. The incidence of mesenchymal tumors (leiomyosarcoma) in the stomach and duodenum was higher following treatment with MNNG plus flurbiprofen as compared to the incidence following treatment with MNNG alone or in combination with 16,16-dm-PGE2 (P less than .005). No malignant tumors developed in the gastrointestinal tracts of animals treated with flurbiprofen or 16,16-dm-PGE2 alone or in controls. The higher incidence of gastric and duodenal leiomyosarcomas after treatment with flurbiprofen suggests that reduction of prostaglandin synthesis favored the development of MNNG-induced cancer in mesenchymal tissues of the upper gastrointestinal tract.