The challenge presented by warfarin drug-drug interactions with antibiotics has been extensively cited, but available research has been unable to quantify the scope of this problem in a large, real-world warfarin population. Clark and coauthors conducted a retrospective, longitudinal cohort study of 12 000 patients comparing international normalized ratio (INR) effects among 3 distinct groups of prevalent warfarin users—those who (1) purchased an antibiotic, (2) had a medical visit for upper respiratory tract infection but received no antibiotic, and (3) purchased only a warfarin refill. The mean INR change was negligible in all 3 groups, but the risk of a follow-up INR of 5.0 or greater was higher in both the patients who purchased an antibiotic and had an upper respiratory tract infection compared with the patients who only refilled their warfarin. Antibiotics that interfere with warfarin metabolism posed a greater risk of a follow-up INR of 5.0 or greater than antibiotics thought to disrupt vitamin K synthesis or without a known interaction mechanism. Katz provides additional comment in an Editor’s Note.