Objective: To compare clinicopathological features and long-term outcome in gastric cancer patients coming from high-risk and low-risk areas of Italy. Summary Background Data: Better Survival rates have been reported from countries with higher incidence of gastric cancer. Methods: Data regarding 829 patients coming from Tuscany (group A) and 143 patients coming from Southern Italy (group B) were analyzed. Mean follow-up time was 56 +/- 57 months; it was 85 +/- 63 months in surviving patients or not tumor-related deaths. Prognostic factors were investigated by multivariate analysis with Cox proportional hazard model after verifying the assumption of proportionality of the risk associated with covariates. Results: Lauren diffuse-mixed histotype, younger age, extended lymphadenectomy, and advanced stages were more common in group B. Gastric cancer-related 10-year survival probability was 48% in group A versus 29% in group B (log-rank test: P < 0.001). By multivariate analysis, geographic area was confirmed as a significant prognostic factor (hazard ratio for group B vs. group A: 1.52, 95% confidence interval: 1.12-2.06, P = 0.006). The influence of this factor on log-term survival was independent from other clinical, surgical, and pathologic factors, and was notable in neoplasms involving the serosa (10-year survival probability: 15% in group A vs. 3% in group B, log-rank test: P = 0.005). Conclusions: Patients coming from low-risk area of Italy showed distinct pathologic features, more advanced stage, and worse prognosis when compared with patients coming from high-risk area. These findings may be indicative of different tumor biology, and may contribute to partly explain worldwide geographic variability in prognosis reported in different series.