Previous studies suggest overrepresentation of particular polymorphisms within the Helicobacter pylori CagL protein hypervariable motif (CagLHM) in gastric cancer-associated isolates. However, these disease correlations were geographically variable and ambiguous. We compared the disease correlation of several hundred geographically diverse CagL sequences and identified 33 CagLHM sequence combinations with disparate geographical distribution, revealing substantial worldwide CagLHM diversity, particularly within Asian countries. Notably, polymorphisms E59 and I60 were significantly overrepresented, whereas D58 and E62 were underrepresented, in gastric cancer-associated H. pylori isolates worldwide. Thus, CagLHM regional diversity may contribute to the varied prevalence of H. pylori-related gastric cancer observed in diverse populations.