Oral anticoagulants achieve an antithrombotic effect only several days after initiation of treatment. A rapid decline of the vitamin-K dependent natural anticoagulants (proteins C and S) during this period might result in a prothrombic phase. We addressed this question by measuring the rates of decline of these proteins, as well as the vitamin K dependent procoagulants, in two groups of patients: A "high dose group" (n = 7), who received a single 40 mg dose of warfarin, and a "low dose group" (n = 20), who received daily individually adjusted doses. In the high dose group an early and marked decline of factor VII:C and protein C antigen was observed, while levels of the other vitamin K dependent factors were still relatively high. In the low dose group, all these proteins declined more gradually. Mean +/- SD of protein C antigen level at 46 hr was 56 +/- 12% in the low dose group, and only 44 +/- 6% (p less than 0.05) in the high dose group. We conclude that during the initiation of warfarin therapy there is a transient prothrombotic phase, which is less marked in patients given daily adjusted doses.