Abstract. Previously, we have investigated the effects of short-term (minutes to hours) and long-term (weeks to months) stimulation with gastrin on the histamine-producing enterochromaffin-like (ECL) cells in the oxyntic mucosa of rat stomach. The present study examines the response of the ECL cells of freely fed rats to sustained hypergastrinemia over a time span of a few hours to four weeks. Sustained hypergastrinemia was induced by the continuous subcutaneous infusion of human Leu15-gastrin-17. The histidine decarboxylase (HDC) activity and histamine concentration in the oxyntic mucosa were monitored throughout the study. ECL cell profiles in electron micrographs were analysed planimetrically. The HDC activity displayed a 4-fold increase within the first two days. Subsequently, it remained at a plateau. The histamine concentration increased 2- to 3-fold in response to gastrin. The rise in histamine was slower than the rise in HDC activity. At no time point was there a reduced concentration of histamine. The ECL cells increased in size after 4days of hypergastrinemia, reaching a maximum cell profile area after 2weeks and remaining enlarged for the duration of the study. The secretory vesicles were reduced in number after 1day, returning gradually to the pre-stimulation value thereafter; their volume density remained reduced during the 6-day observation period. Vacuoles started to appear after 1day of hypergastrinemia and their number and volume density increased, reaching a maximum after 4days. The number and volume density of the microvesicles increased and plateaued after 2days of hypergastrinemia. The number of granules per cell profile was unaffected but their volume density was greatly reduced after 4days of hypergastrinemia (reflecting the ECL cell hypertrophy). The present findings establish the time course of activation of the ECL cells in response to sustained hypergastrinemia over a time span of a few hours to four weeks; a new steady state situation at a high level of activity has been established after about a week.