Prostaglandins (PGs) are known to be involved in inflammatory and nociceptive processing. Since the discovery of at least two isozymes of cyclooxygenase (COX), inhibition of COX-2 has been suggested to be responsible for the therapeutic effects of non-steroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of a rather selective COX-2 inhibitor, NS-398 (0.3–27 mg/kg i.p.), were studied using the rat formalin test as a model of acute nociception. Diclofenac (non-selective COX inhibitor; 0.3–27 mg/kg i.p.) was used as a control. NS-398 revealed antinociceptive activity only at a dose (27 mg/kg) which results in plasma concentrations which most likely do not selectively inhibit COX-2. By contrast, diclofenac inhibited formalin-induced flinching behaviour over the whole dose range tested. Our results suggest that PGs mediating nociception in the formalin test of the rat are most likely produced via the COX-1 as well as COX-2 pathways. Thus, in an acute model of nociception a non-selective COX inhibitor may offer advantages as compared to a selective COX-2 inhibitor.