Excedrin is over-the-counter pain reliever containing acetaminophen, caffeine and aspirin as active ingredients of this drug composition. Acetaminophen (paracetamol) is used as analgesic and pain reliever. It is a neutral compound with low hydrophobicity. Aspirin or acetylsalicylic acid is used as analgesic and anti-inflammatory component of many OTC compositions. It is weakly acidic and slightly hydrophobic compound. Caffeine is xanthine alkaloid which is psychoactive stimulant drug. All four compounds are separated on mixed-mode Primesep 100 HPLC column with acetonitrile/water/TFA mobile phase. In this HPLC application compounds are retained by reversed phase mechanism. This HPLC method is short and robust.