In this study, which is the first of its kind using normal tissue samples that are very difficult to obtain, we have investigated the hypothesis that smoking protects against ulcerative colitis by altering the colonic mucosal formation of prostaglandins and related substances. Colonic mucosa biopsied from healthy young men produced prostaglandin E, 6-keto-PGF1 alpha (formed from PGI2), leukotriene B4 and leukotriene C4/D4/E4 as determined by radioimmunoassay. With each substance, the median yield was lower in the group of smokers who smoked 3 cigarettes in the 2 h before biopsy, than in the non-smokers. However, with each eicosanoid the statistical probability approached only the 10% level, but the fact that the trend was the same for all eicosanoids somewhat strengthens the possibility of a real difference between the groups.