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SUMMARY The effect of H2-receptor blockade on intragastric acidity was studied in nine normal males. The pH of their gastric contents was measured at hourly daytime and two hourly nighttime intervals for 48 hours. The subjects ate identical meals, drank identical volumes of fluid, and smoked the same number of cigarettes during the two study days. Their physical activity was unrestricted in a ward environment. Blood cimetidine and plasma gastrin were measured in serial blood samples. The nine subjects were treated in random sequence with cimetidine 0 8-1 *0 g on one day and placebo capsules on the other. The drug was given in four divided doses: four subjects received it before, and five after, the three main meals. All took the fourth dose at bedtime. Replicate studies in an additional subject given placebo on both study days showed good reproducibility (r = 0O80, p < 0 01). Cimetidine therapy decreased intragastric acidity in all nine subjects. The decrease was similar in the two groups taking the drug before or after meals, mean 24 h intragastric hydrogen ion activity being lowered by 70 and 72 % respectively. Nocturnal anacidity was recorded in only two of 45 samples. Administration of cimetidine before meals produced earlier and higher drug blood levels than post-prandial medication, but when it was taken after food the blood levels were highest at the time when the buffer capacity of the food was waning. Blood concentrations of cimetidine exceeded the secretory IC50 level for most of the time between doses. The results show that cimetidine 0 8-1 .0 g/day in four divided doses produces a striking and consistent decrease of intragastric acidity. Although variation in the timing of the dose in relation to meals did not affect the decrease of acidity, the absorption data suggest that patients should take the drug after meals.Cimetidine is a new histamine H2-receptor antagonist, which in man has a potency similar to metiamide for the inhibition of acid secretion stimulated by pentagastrin or food (Black et al., 1972;Black et al., 1973;Mainardi et al., 1974;Brimblecombe et al., 1975;Burland et al., 1975;Pounder et al., 1975a;Henn et al., 1975;.The thiourea residue in metiamide, which is thought to have been responsible for the reversible marrow depression that occurred in seven patients receiving the drug, has been replaced by a cyanoguanidine moiety in cimetidine.In order to determine the optimal time of medication before starting clinical trials of the new com-