H. pylori infection has recently been associated with various vascular disorders. The aim of this study was to investigate its role in primary headache, a pathology strictly associated with vascular alterations. A total of 200 subjects affected by primary headache were evaluated. H. pylori infection was diagnosed by the 13C urea breath test. Headache was classified in tension-type headache, cluster headache, and migraine with or without aura. Prevalence of H. pylori infection and gastrointestinal (GI) symptoms were evaluated. H. pylori infection was found in 40% of the patients; prevalence of migraine without aura was found to be significantly greater in infected patients. The positive group showed no significant differences in the prevalence of the GI symptoms evaluated. In 30 infected patients, it was assessed whether the eradication of the bacterium was able to reduce frequency, intensity, and duration of clinical attacks of headache. After eradication, clinical attacks of headache completely disappeared in 17% of patients. Moreover, intensity, duration, and frequency of headache attacks were reduced in 69% of the remaining subjects. In conclusion, H. pylori infection is common in primary headache; bacterium eradication appears to be related to a significant reduction in clinical attacks of the disease.