The discovery of burimamide by Black and associates1 provided the first example of a specific antagonist of the histamine H2 receptor. This prototype, although of low intrinsic inhibitory activity, constituted a lead for the development of the more potent inhibitors metiamide2 and cimetidine3. The clinical efficacy of the latter as a gastric antisecretory drug stimulated a search for agents with improved potency, longer duration of action, and a lower potential for side effects. Recently, highly potent nonimidazole H2 inhibitors, such as ranitidine4 and tiotidine5, have been described. Structural comparison of these drugs reveals three fundamental units: a substituted heterocycle joined by a 2-thiabutyl connecting chain to an acyclic end group or "urea equivalent" such as cyanoguanidine or diaminonitroethene. This report describes a new class of histamine H2 receptor antagonists wherein 3,4-diamino-1,2,5-thiadiazole oxides function as the "urea equivalent". Representative examples (la-f)6 are presented to illustrate structure-activity relationships within the series and for comparison with reference drugs (Table I).