The molecular mechanisms leading to gastric carcinogenesis still remain unclear. Recently, several studies demonstrated that over-expression of guanylyl cyclase C (GCC) has been detected in intestinal-type gastric cancer (GC) and precursor lesions. Our objective was to explore the expression levels of GCC and endogenous ligands guanylin (GN) and uroguanylin (UGN) and the correlation between Helicobacter pylori (H. pylori) and GCC, GN, and UGN expressions in patients at different stages from normal mucosa to superficial gastritis, atrophic gastritis, intestinal metaplasia (IM), dysplasia, and finally adenocarcinoma. The expression of GCC and GN was absent in the distal normal gastric tissues and superficial gastritis in all cases, whereas they were measured in IM, dysplasia, and GC. The expression of GCC and GN was closely related to intestinal-type GC. From superficial gastritis to gastric carcinomas, the H. pylori positive rate was 19.7, 33.3, 69.6, 80.0, and 82.1%, respectively. The positive correlation was found between GCC and GN in IM, dysplasia, and GC. Also, the positive correlation was found between GCC, GN, and H. pylori infection in them. These results demonstrate that the detection of GCC and GN will be beneficial to diagnosis human gastric carcinoma and precancerous lesions. Ectopic expression of GCC and GN in human gastric mucosa and H. pylori infection may play an important role in the carcinogenesis of the intestinal-type GC.