Some patients with hypergastrinemic achlorhydria may have false-positive secretin provocation as an exaggeration of the normal gastrin response to secretin, presumably related to an increased, or more responsive, antral G-cell mass. To test this hypothesis, we reviewed our experience with secretin provocation in normogastrinemic subjects with presumed normal antral G-cell mass (normal—17, duodenal ulcer—13) and in patients with hypergastrinemia related to changes in antral G-cells (vagotomy—5, hypochlorhydria—7, achlorhydria—10). Basal serum gastrin (mean ± SEM) was progressively higher for each group; normal (42 ± 3 pg/ml), duodenal ulcer (53 ± 4 pg/ml), vagotomy (226 ± 54 pg/ml), hypochlorhydria (346 ± 92 pg/ml), achlorhydria (844 ± 100 pg/ml). On selective analysis of only those with gastrin rises, significant differences (p < 0.05) in peak gastrin change were found between achlorhydria (93 ±21 pg/ml) compared with all other groups and between hypochlorhydria (40 ± 12 pg/ ml) versus normal (6 ± 1 pg/ml). Linear regression in these responders showed a significant correlation (p < 0.001) between basal gastrin and peak gastrin change after secretin. There were no false-positive secretin provocation tests, but four achlorhydric patients had gastrin rises >100 pg/ml, whereas no patient in the other categories had rises above 90 pg/ml. Our results support the concept that patients with hypergastrinemic achlorhydria tend to have greater G-cell responsiveness to secretin provocation, which may account for the false-positive results in some such patients.