Failure of acid suppression by H2-receptor antagonists has been observed, and recently we have found a higher frequency of patients with inadequate antisecretory response among patients with cirrhosis of the liver. In the present study comprising 16 cirrhotics with inadequate antisecretory response to 300 mg of ranitidine, we tested the effect of 40 mg omeprazole. Nighttime intragastric pH was continuously monitored, and a rise in the intragastric pH above 4.0 for more than 6 h following the oral dose at 18.00 h was considered as response. The median pH profile during the omeprazole treatment was significantly higher than with ranitidine (p ≤ 0.001). In contrast to 300 mg ranitidine, which despite sufficient plasma levels 2 and 4 h after intake (762 ± 431 and 802 ± 668 ng/ml) resulted in a rise in the nighttime intragastric pH above 4 only for 1.8 ± 1.7 h, after omeprazole for at least 5 days, the intragastric pH was for 10.1 ± 2.4 of 12 h above 4 during the night (p < 0.001). The omeprazole plasma levels were 611 ± 323 and 881 ± 533 ng/ml after 2 and 4 h. The data obtained with intragastric pH monitoring indicate that the H+K+-ATPase inhibitor omeprazole is able to overcome the H2-blocker resistance in cir