A 61-year-old man with a mitral valve replacement who had been therapeutically anticoagulated with warfarin for the previous 12 months had a decrease in his prothrombin time after starting treatment with griseofulvin. Over a three-month period his warfarin dose was gradually increased. An overall increase of 41 percent was needed to maintain therapeutic anticoagulation. A reduction in the griseofulvin dose resulted in an increase in the prothrombin time and, subsequently, a lowering of the warfarin dose. No other potential causes for the decreased response to warfarin were identified. While there previously has only been limited documentation of this interaction, it appears that a substantial decrease in the response to warfarin can occur following initiation of griseofulvin therapy. Immediate adjustment of the warfarin dose at the onset of griseofulvin therapy is not needed. However, the prothrombin time should be monitored at weekly intervals and the dose of warfarin increased according to the patient's response.