To determine the relation between a history of tonsillectomy and the prevalence of colonization by Helicobacter pylori (HP), we conducted an observational, cohort study at the University of Oklahoma Hospital over a 13-month period. Subjects under-going upper endoscopic evaluation and antral biopsies for HP at the University of Oklahoma Hospital formed the database. The indication of the endoscopy and biopsies was determined by the endoscopist. The antral biopsy specimens were tested for HP using a rapid urease test. We recorded the patient's name, age, gender, race, history of smoking, and history of appendectomy or tonsillectomy. One hundred nine subjects constituted our database. There was no difference in age, gender, or smoking between the HP+ (n = 37) and HP- (n = 72) groups. The ability to pay for healthcare through a third-payor party also was similar. The prevalence of prior tonsillectomy was 30.6% in HP- group versus 5.4% in HP+ group (p < 0.01). In contrast, the prevalence of prior appendectomy was 21.6% in HP+ group versus 23.6% in HP- group (p = not significant). Multiple regression was carried out to account for confounding variables. The model showed that only white race and tonsillectomy were significantly related to the presence of HP colonization. Both appendectomy and health insurance, which were the surrogate markers for access to healthcare and socioeconomic status, were insignificant. We conclude that a history of tonsillectomy is associated with decreased prevalence of HP colonization.