This paper critically reviews the current literature on extragastric diseases associated with Helicobacter pylori infection, with an emphasis on methodologic issues that complicate interpretation of study findings. This review reveals common study limitations and overall uncertainty that H. pylori infection plays a role in extragastric diseases, although such a role has not been clearly ruled out for specific diseases of relevance. Evidence suggests that anti-H. pylori therapy may lead to improvement of a few extragastric diseases, in particular, idiopathic thrombocytopenic purpura, iron deficiency anemia, and chronic idiopathic urticaria, but the data from randomized controlled trials are insufficient to confirm this beneficial effect; if the benefit of anti-H. pylori therapy for specific diseases is real, it is not clear if it results from removing H. pylori-specific injurious effects, eliminating some other infectious pathogen, or reducing the total infectious burden.