Purpose: To examine the risk factors for Gastrointestinal (GI) bleed in patients on warfarin and proton pump inhibitors (PPI) therapy. Methods: The study is a retrospective review of medical records of 626 Veteran male patients, identified from the pharmacy database for having received warfarin for at least 2 weeks between the years 2000 and 2005. Variables like age, NSAID, aspirin, selective serotonin receptor uptake inhibitor (SSRI), PPI and antiplatelet use, history of GI bleed, history of GERD, chronic renal failure (CRF; serum creatinine > 1.5 mg/dl), history of peptic ulcer disease (PUD), Prothrombin Time (PT) and International Normalized Ratio (INR) values at the time of GI bleed were collected. Clinical characteristics of subjects who suffered a GI bleed were compared with subjects who did not. Spearman Rho correlation was used to study the relationship between INR and the above variables in all subjects and separately in the subset of subjects with and without GI bleed. Chi-square test was used to compare categorical variables and a co-morbid score was calculated by counting the number of the above risk factors in the two groups. Results: Out of 626 subjects, 63 (9.9%) were identified with a GI bleed. The mean age was similar for bleeders 74.8 (SD 10.3) and non-bleeders 72.5 (SD 11.7); p= 0.144. Subjects with GI bleed were more likely to have chronic renal failure (36.5% vs. 12%; p < 0.001), aspirin (36.9% vs. 20.8%; p < 0.001), PPI use (53.9% vs. 35.5%; p < 0.004), history of GI bleed (46% vs. 0.01%; p < 0.001) and history of PUD (12.6% vs. 0.05%; p < 0.03). GI bleed (r = 0.27; p <.001), history of GI bleed (r = 0.09, p < 0.025), SSRI use (r = 0.079, p < 0.048) and PT (r =.93; p < 0.001) were found to have significant positive correlation with INR while INR values were lower in subjects on PPI (r = −0.094; p <.019). After controlling for age and history of GI bleed, PPI use was found to have a significant negative correlation with INR (r = −0.198; p <.008) in all subjects. The co-morbid score, however, was higher in the GI bleed group (2.3, SD = 1.5) than the non-GI bleed group (1.2, SD = 1.2). Subjects who were using PPI had more co-morbidities and significant association with GI bleed (p <.004). Conclusions: Subjects with GI bleed while using PPI have more co morbid conditions as risk factors for GI bleed, the above observations could be a bystander effect.