Chronic Helicobacter (H.) pylori infection, typically of childhood onset, causes upper digestive tract diseases of major impact among socioeconomically marginalized populations. This infection is common in children from ethnic minorities in the United States, and particularly so in immigrant children from Mexico. Prevention measures for H. pylori infection do not yet exist, given limited understanding of what causes either acute or persistent infection. To address this gap, we initiated the Pasitos Cohort Study to follow children from low-income families in the border region that includes El Paso County, Texas, and Ciudad Juarez, Chihuahua. The children were enrolled prior to birth, and are examined at 6-month intervals to observe the natural history of H. pylori infection, and to identify risk factors for acquisition, recurrence, and persistence. This report details the study methods, describes how the cohort was established, and discusses the challenges of compliance with follow up in the border setting. Between April 1998 and October 2000, 1,288 pregnant women were screened for eligibility; 807 of 994 eligible women consented to participate. Birth documentation was obtained for 615 infants, and 472 entered follow up. Successful follow up of this cohort requires resources, including a well-trained, dedicated staff, and incentives, to facilitate and motivate long-term participation. Future findings from this ongoing study will help to fill critical gaps in knowledge regarding the epidemiology of H. pylori infection, and will contribute to the identification of prevention strategies.