A new model for measuring gastric secretory parameters in awake guinea pigs is described. A chronic cannula was surgically implanted in the stomach of each guinea pig. The rates of gastric secretion and changes in intragastric volume were measured using a dye dilution technique. In contrast to previous techniques in small laboratory animals, there was no collection of gastric juice via drainage, no oral intubation for aspiration was involved, no special or sophisticated equipment was used, no anesthesia was employed, and there was no stress associated with acute surgery. This method offers a valuable advantage by combining the chronic gastric cannula with a dye dilution technique in that the same animal can be used several times and finally, several gastric secretory parameters can be measured simultaneously. The animals were used from 3 weeks to 10 months after surgery and as many as 15 studies were performed on the same guinea pig. Samples were collected at 10-min intervals and analyzed for acid and dye concentration from which the onset and kinetics of gastric secretion were followed. Basal gastric secretion (11.8 ± 1.6 μeq/kg/min; all mean ± 1 SEM) was increased within 20 min after subcutaneous infusion of histamine (30 μg/kg/hr) and peaked by 40-60 min at a mean acid output rate of 41 ± 3 μeq/kg/min. Histamine also increased the intragastric volume from 6.3 to 13.4 ml as it increased fluid output from 1.6 ± 0.1 ml/10 min to 3.4 ± 0.2 ml/10 min. The increase in acid output caused by histamine was inhibited by the H2-antagonists cimetidine (3 μmole/kg) and ranitidine at 0.5 μmole/kg. Omeprazole (1.2 μmole/kg), an HK-ATPase inhibitor, almost abolished acid output under both basal and histamine-stimulated conditions. Thus, the present method is simple and suitable to study the physiology and pharmacology of gastric secretion in the guinea pig with a particular emphasis on the action of histamine. Furthermore, because of the species involved, there is also a significant economical advantage and the guinea pig can also be used as a potential model for studying experimental ulcer.