Guidelines for osteoarthritis (OA) management recommend paracetamol (acetaminophen) as the most appropriate first-line analgesic for mild to moderate pain. Standard paracetamol requires four times daily dosing. Drug compliance and convenience are inversely related to daily dose frequency. Compliance is a pivotal component of the successful management of OA pain and is influenced by patient preferences or beliefs. The added convenience of three times daily dosing may enhance compliance and, therefore, pain relief. This multicentre, randomized, open-label, two-way crossover, phase IV study is the first to evaluate patient preference with a sustained-release paracetamol tablet formulation designed for three times daily dosing. Compared with standard paracetamol tablets dosed four times daily, the sustained-release formulation was preferred in a 2:1 ratio, provided better overall joint pain relief, resulted in higher levels of satisfaction in subjects with OA of the knee and has the potential to improve patient compliance and, therefore, pain control.