Acetaminophen (paracetamol) and other analgesic/antipyretic drugs such as dipyrone have been postulated to act centrally through inhibition of cyclooxygenases (COXs). COX activity in lipopolysaccharide-stimulated mammalian leukocytes, microglial cells, and platelets is inhibited by these drugs at physiological concentrations. Yet purified COX enzymes are poorly inhibited by acetaminophen, particularly under conditions of high oxidant tone and elevated substrate levels. This suggests the presence of cell-specific differences that govern COX inhibition by these drugs. COX-3, a variant of COX-1, has been found in canine brain and is inhibited by acetaminophen and dipyrone at physiological concentrations. Additionally, other new COX-1-derived proteins called PCOX have been identified that do not make prostaglandins but apparently bind heme and may have other enzymatic properties. Antibodies specific for these variants detect analogous proteins in human tissues. Expression of COX variants is postulated to be an integral part of the mechanism of action of analgesic/antipyretic drugs.