In Latin America, gastric cancer is a leading cancer, and countries in the region have some of the highest mortality rates worldwide, including Chile, Costa Rica, and Colombia. Geographic variation in mortality rates is observed both between neighboring countries and within nations. We discuss epidemiological observations suggesting an association between altitude and gastric cancer risk in Latin America. In the Americas, the burden of gastric cancer mortality is concentrated in the mountainous areas along the Pacific rim, following the geography of the Andes sierra, from Venezuela to Chile, and the Sierra Madre and Cordillera de Centroamérica, from southern Mexico to Costa Rica. Altitude is probably a surrogate for host genetic, bacterial, dietary, and environmental factors that may cluster in the mountainous regions. For example, H. pylori strains from patients of the Andean Nariño region of Colombia display European ancestral haplotypes, whereas strains from the Pacific coast are predominantly of African origin. The observation of higher gastric cancer rates in the mountainous areas is not universal: the association is absent in Chile, where risk is more strongly associated with the age of H. pylori acquisition and socio-economic determinants. The dramatic global and regional variations in gastric cancer incidence and mortality rates offer the opportunity for scientific discovery and focused prevention programs.