Nafcillin, a beta-lactam semisynthetic penicillin, is highly resistant to penicillinase and is similar to other penicillins except that it is primarily metabolized in the liver. It is believed that nafcillin causes CYP3A4 enzyme induction which decreases warfarin's half-life. The onset of CYP3A4 induction by nafcillin occurs within the first 7 days, but maximal effects may take up to 2 weeks. Once nafcillin is discontinued, the effects persist for several weeks. A 79-year-old male with a history of atrial fibrillation and a 53-year-old male with a history of recurrent venous thromboembolism required significantly higher weekly warfarin doses during courses of nafcillin therapy. Both patients required a 2.5-3.5-fold increase from their baseline weekly warfarin dose to achieve therapeutic international normalized ratios (INRs) while on nafcillin. Traditional protocol-driven warfarin management can result in suboptimal anticoagulation in patients on warfarin and nafcillin.