Paracetamol and phenylephrine are frequently associated in pharmaceutical formulations against the common cold. In this work, the proportion of organic modifier of acetonitrile–water mixtures used as mobile phases were optimized in order to separate the paracetamol (acetaminophen) and phenylephrine. The separation was accomplished using a Synergi Polar RP (4 μm, 150 x 4, 6 mm I.D.) column. The best chromatographic separation was carried out using acetonitrile-water at 5:95, %v/v, containing 65 mM phosphoric acid. The developed method was proposed for the simultaneous separation of these drug active compounds in liquid dosage form. Intra- and inter-day repeatabilities evaluated at two different drug concentrations (10-25 μg/mL for phenylephrine hydrochloride, 150- 500 μg/mL for paracetamol). The drug amounts found in the analysis of commercialised preparation agreed with those declared by the manufacturer.