The acid-inhibitory action of H2-receptor antagonists was shown to decrease after one to two weeks of dosing in healthy volunteers. This tolerance was evaluated in three randomized, placebo-controlled trials with the H2-receptor antagonists famotidine, 40 mg given after the evening meal for 28 days; ranitidine, 300 mg four times a day for seven days followed by 300 mg at night until day 28; and ranitidine, 300 mg three times a day vs 300 mg at night for 14 days. Continuous 24-hr pH monitoring with glass electrodes was performed under fed conditions. The median 24-hr pH decreased from 3.2 on day 1 with famotidine 40 mg to 1.9 on day 28 (P less than 0.0012). After seven days of dosing with ranitidine 300 mg four times a day the median 24-hr pH dropped from 5.0 on day 1 to 3.0 on day 7 (P less than 0.001) and then to 2.2 with ranitidine 300 mg at night on day 28. With ranitidine 300 mg three times a day the median 24-hr pH fell from 4.3 on day 1 to 2.4 on day 14 (P less than 0.0005). With ranitidine 300 mg at night the respective pH values were 2.5 and 1.8 (P less than 0.003). Tolerance to H2-receptor antagonists given in a single evening dose was only evident during the night, whereas tolerance occurred throughout the day and night with the three- and four-times-a-day regimens. A large increase in the interindividual variability of pH response was seen during the nighttime.