Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first-line treatment in all pain conditions by WHO. We performed a systematic literature review to evaluate the efficacy of acetaminophen when used for chronic pain conditions. Applying three broad search strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1551 hits were obtained. After cross-reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than 2 weeks with placebo were included. The review was conducted according to the PRISMA guidelines. All studies were conducted in patients with hip- or knee osteoarthritis and six of seven studies had observation periods of less than 3 months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended.