Objective: The aim of this study was to study the changes in occurrence of esophageal, stomach and colon cancers (cancers of interest) over the last 30 years in Iran. Material and Methods: Cancer cases referred to two main cancer centers in the country (the Shiraz cancer center and the Tehran cancer center) during last 30 years and published by the two centers were utilized. Morbidity odds ratios (MOR) were used to study trend in the occurrence of each cancer site in each center. For this purpose the cancers of interest were considered as cases; childhood cancers as controls; and calendar year as exposure. A regression line was fitted to morbidity odds ratios over years and the slope of the regression line was considered to indicate the overall trend. MORs and 95% CIs comparing the last five and first five years were computed to measure the magnitude of the change over time. Result: The overall trend for esophageal cancer was decrease (slopes = -0.02 for Shiraz and -0.03 for Tehran); for stomach was increase (slopes = 0.04 for Shiraz and 0.08 for Tehran), and for colon cancer was sharp increase (slopes = 0.02 for Shiraz and 0.10 for Tehran). The magnitude of changes showed stomach cancer to increase by 35% in Shiraz (MOR = 1.35 with 95% CI 1.1, 1.65) and 13% in Tehran (MOR = 1.13 with 95% CI 0.96, 1.38), esophageal cancer to decrease by 20% in Shiraz (MOR = 0.82 with 95% CI 0.62, 1.11) and 50% in Tehran (MOR = 0.52 with 95% CI 0.45, 0.60), and colon cancer to increase by 65% in Shiraz (MOR = 1.65 with 95% CI 1.26, 2.16) and 82% in Tehran (MOR = 1.82 with 95% CI 1.52, 2.25). Conclusion: During the last thirty years the occurrence of major GI cancers has changed in Iran with sharp increase in colon cancer, slight to moderate increase in stomach cancer and sharp decrease in esophageal cancer.