Little is known about proton pump inhibitor (PPI) or H(2) receptor antagonist (HA) prescription patterns or regarding use of predictors in hemodialysis patients. Proton pump inhibitor and HA prescribing patterns were investigated in 8628 hemodialysis patients from seven countries enrolled in the prospective, observational Dialysis Outcomes and Practice Patterns Study. Logistic regression examined predictors associated with PPI and HA use, adjusting for age, sex, country, time with end-stage renal disease, medications, 14 comorbid conditions, and the association between the number of comorbid conditions and the prescription of gastrointestinal (GI) medications. In a cross-section from February 1, 2000, 3.4% to 36.9% of patients received an HA and 0.8% to 26.9% took a PPI, depending upon the country. From 1996 to 2001, the prescription of HAs declined while PPI use increased. Facility use of HAs and PPIs ranged from 0% to 94% of patients. H2 receptor antagonist or PPI use was significantly and independently associated with age, narcotic use, corticosteroids, acetaminophen, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, selective serotonin reuptake inhibitors, coronary artery disease history, cardiovascular diseases other than hypertension or congestive heart failure, peripheral vascular disease, pulmonary disease, and GI bleed. Proton pump inhibitors or HAs were more likely to be prescribed in Italy, Spain, and the United Kingdom than in the United States. The odds of PPI prescription increased if serum phosphorus <5.5 mEq/L or serum albumin <3.5 g/dL. Prescription of GI medications was associated with many comorbidities and use of several medications. Extreme variability of prescription patterns suggests that there is no standard approach in treatment practices.