To establish an RP-HPLC method for determination of ibuprofen sustained-release capsules' related substances of 2-(4-butylphenyl)-propionic acid and 4-isobutylacetophenone. The C18 column was used. The mobile phase was 0.5 volumes of phosphoric acid, 340 volumes of acetonitrile and 600 volumes of water, diluted to 1000 volumes with water. The detection wavelength was at 214 nm, and the flow rate was 2 mL/min. The linear range of ibuprofen sustained-release capsules' related substances of 2-(4-butylphenyl)-propionic acid was 3.00-9.00 μg/mL (γ = 0.9992). The average recovery rate was 99.9%, and RSD = 0.82%. Detection limit was 0.13071 μg/mL. The linear range of ibuprofen sustained-release capsules' related substances of 4-isobutylacetophenone was 1.19-7.14 μg/mL (γ = 0.9995). The average recovery rate was 100.2%, and RSD = 1.00%. Detection limit was 0.1428 μg/mL. The method is simple and accurate with good reproducibility, resolution and sensitivity. It provides a new and reliable means for the quality control to content determination of ibuprofen sustained-release capsules of 2-(4-butylphenyl)-propionic acid and 4-isobutylacetophenone.