IGF family proteins play a pivotal role in regulating cell growth and apoptosis in normal and tumour tissues. IGFBP-3 is the major binding protein of IGFs and modulates the bioactivity of IGFs. To examine the role of IGFBP-3 in gastric cancer, an IGFBP3 promoter polymorphism, and serum and gastric mucosal levels of IGFBP-3 were assessed in two independent groups of patients (396 and 117 patients, respectively) with gastroduodenal diseases. There was no significant association between IGFBP-3 polymorphism and different gastroduodenal diseases ( p = 0.6), but a significantly higher frequency of CC, a genotype related to lower levels of serum IGFBP-3 previously, were observed in patients with antral intestinal metaplasia when compared with those without this pre-malignancy ( p = 0.04). Similarly, data from another independent group of patients further showed that patients with antral or corpus intestinal metaplasia had significantly lower serum levels of IGFBP-3 than those without these changes ( p = 0.03 and 0.04, respectively). Furthermore, the percentage of positive IGFBP-3 staining in tumour tissue was significantly higher in patients with well or moderately differentiated tumours than those with poorly differentiated tumours ( p = 0.04), indicating that IGFBP-3 may be associated with a better prognosis. In conclusion, our study suggests that IGFBP-3 may be protective against the development of gastric adenocarcinoma by preventing the formation of intestinal metaplasia and improve the prognosis of gastric cancer.