We measured serum pepsinogen I (sPG-I) in 269 patients undergoing upper GI endoscopy and then classified by endoscopic diagnosis, gastric mucosal histology, and smoking habit. Both ulcer-free and duodenal ulcer smokers had significantly higher sPG-I levels than their non-smoking controls. In contrast, sPG-I values were not different in smokers and non-smokers with gastric ulcer. In ulcer-free smokers the overall increase in sPG-I simply reflected the high prevalence of patients with superficial gastritis and elevated sPG-I levels. Conversely, in duodenal ulcer smokers the increase in sPG-I, which was related to the number of cigarettes smoked daily, was not an epiphenomenon of concomitant gastritis. The smoking-induced increase in sPG-I in duodenal ulcer is proposed to reflect an augmented pepsin secretory capacity, which can be of aetiologic significance in the association between cigarette smoking and duodenal ulcer.