Most multivitamin supplements contain far less vitamin K(1) than thought to affect warfarin anticoagulation. Having described 3 patients with multivitamin-warfarin interactions, we hypothesized that vitamin K(1)-depleted patients are sensitive to even small increments. Therefore, we compared the effect of a vitamin K(1)-containing multivitamin on warfarin anticoagulation between patients with low versus normal vitamin K(1) status. We screened 102 warfarin-treated patients and recruited nine with "low" (< 1.5 mcg/L, 10(th) percentile) (group 1) and 7 with "normal" (>4.5 mcg/L, median) (group 2) total vitamin K(1) plasma levels (vitamin K(1) + vitamin K(1) 2,3-epoxide). Patients received one multivitamin tablet containing 25 mcg of vitamin K(1) daily, for 4 weeks (period 1). A predefined algorithm was used to adjust warfarin doses if the INR was outside the therapeutic range. Patients requiring warfarin increments were then switched to 4 weeks of a vitamin K(1)-free multivitamin supplement (period 2). During period 1, subtherapeutic INRs occurred in 9/9 and 1/7 patients in group 1 and 2, respectively (p <0.001). In group 1, INR decreased by a median of 0.51 (p <0.01), and warfarin dose had to be raised by 5.3% (p <0.01), whereas INR and warfarin dose did not change significantly in group 2. During period 2 (7 patients), there were trends towards decreased total vitamin K(1) and rising INRs associated with significantly lower warfarin doses. We conclude that vitamin K(1)-containing multivitamins reduce INR in patients with low vitamin K(1) status. Our study suggests that vitamin K-depleted patients are sensitive to even small changes in vitamin K(1) intake.