Synthesis, structural characterization, and pharmacological profile of a series of Hz-antagonists able to release nitric oxide (NO) are reported. These compounds were obtained by using appropriate spacers to join H-2-antagonistic pharmacophoric groups related to lamtidine and tiotidine to different NO-donor moieties such as esters of HNO3, nitrosothio groups, and benzenesulfonyl-substituted furoxans. All of the compounds were tested for their NO-donor properties. Furthermore, the hybrid structures synthesized, together with some selected reference compounds, were tested for their H-2-antagonistic properties, both in vitro and in vivo, and for their gastroprotective effects. Only the hybrid compounds were able both to antagonize histamine effects on guinea-pig papillary muscle and to display in vivo antisecretory and gastroprotective action. The best results were obtained with the lamtidine/furoxan hybrid structure.