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Study Objective: To compare the differences between the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions in patients receiving therapeutic doses of warfarin., Design: Retrospective medical record review., Setting: Large academic Veterans Affairs health care system., Patients: Twenty-four patients who received concomitant therapeutic doses of warfarin and at least one dose of a fluoropyrimidine--5-fluorouracil or capecitabine--between January 2004 and May 2008., Measurements and Main Results: The primary outcome was mean change in international normalized ratio (INR) from baseline to end of 90-day study period. Only patients who were taking warfarin before starting either fluoropyrimidine-based chemotherapy were included in the primary analysis. Of the 24 eligible patients, 15 (9 receiving 5-fluorouracil, 6 receiving capecitabine) were taking warfarin before receiving either fluoropyrimidine. No significant differences were noted in the average weekly warfarin dose or baseline INR between the 5-fluorouracil and capecitabine groups. The mean change in INR for patients taking warfarin before fluoropyrimidine use was 4.62 in the 5-fluorouracil group compared with 5.11 in the capecitabine group (p=0.87). The capecitabine group had a similar proportion of patients achieving an INR above 9 while taking warfarin compared with the 5-fluorouracil group (17% vs 22%). In those patients who required a warfarin dosage reduction, the dose was reduced by 38% and 41% in the 5-fluorouracil and capecitabine groups, respectively. No significant differences in bleeding events were reported within 90 days of concurrent use of either fluoropyrimidine with warfarin., Conclusion: Our study suggests that in patients receiving concomitant warfarin and a fluoropyrimidine, no significant differences in INR elevation or bleeding events were noted with 5-fluorouracil compared with capecitabine.