Paracetamol (acetaminophen) is routinely advised when non-steroidal anti-inflammatory drugs (NSAID) are necessary during oral anticoagulant treatment (OAT) because it has no relevant effect on the primary hemostasis. However, in a recent case-control study a dose-related effect was observed of paracetamol intake on the International Normalized Ratio (INR) values making its use controversial during OAT. Our objectives were to determine the effect of paracetamol on the INR values during OAT independent of underlying illness. A double-blind randomized controlled trial in which 31 out-patients on coumarin oral anticoagulant therapy with phenprocoumon, aged 18-70 years, with a planned treatment duration of more than 12 weeks, and an INR target range of 2.5-3.5, were included. Patients were randomized for placebo (10 patients), paracetamol 1500 mg daily (11 patients) or paracetamol 3000 mg daily (10 patients) for 14 days during the stable phase of coumarin OAT and INR values at day 1, 8, 15, 22 and 29 were measured. At day 8 a mean rise of 0.46 INR was seen in both paracetamol groups compared to placebo. At day 15 there was no difference between placebo and paracetamol 1500 mg daily, and a small mean rise of 0.22 INR in the paracetamol 3000 mg daily group. The sustained use of paracetamol (acetaminophen) during oral anticoagulant therapy in itself does not provoke clinically relevant INR changes. Any important INR rise will predominantly be the result of the illness necessitating the intake of this medication. A difference has to be made between those patients taking paracetamol (acetaminophen) for pain relief or as an antipyretic during infectious diseases.