Acetaminophen and aspirin are the drugs of choice used to relieve the symptoms of common headache. Acetaminophen, which is also called paracetamol, is widely used as a pain reliever (analgesic) and fever reducer (antipyretic). Because of its fast onset (eleven minutes after intake), acetaminophen is very effective. However, every year its misuse (dose exceeding the daily adult limit of four grams) can cause fatal liver damage. This application note presents a modified USP method for the analysis of aspirin, acetaminophen and caffeine using a superficially porous particle column and a PerkinElmer® UHPLC platform.