A simple, rapid, precise, accurate and sensitive high performance liquid chromatographic method has been developed for simultaneous determination of ACE inhibitors with hydrochlorothiazide and indapamide in pharmaceutical formulations. 'Design of Experiments' (DoE) using 'central composite design' (CCD) was applied to facilitate method development and optimization. Mobile phase was optimized utilizing response surface methodology using Design Expert software. Chromatographic separation was achieved on HypersilÒ-Gold C 18 (100 · 4.6 mm, 3 lm, Thermo Fisher Scientific, USA), column at 25°C. The mobile phase was 58% buffer (5 mM KH 2 PO 4 , containing triethylamine 0.25 ml/L), 25% acetonitrile and 17% methanol (pH adjusted to 2.8 ± 0.1). The analysis was performed at 215 nm. The mobile phase flow rate was 1.0 ml/min and injection volume 10 ll. The method was validated for linearity, limits of quantitation and detection, accuracy, precision, ruggedness and robustness as per the International Conference on Harmonization (ICH) guidelines. Calibration curves (for lisinopril, hydrochlorothiazide, captopril, imidapril, perindopril, indapamide and trandolapril) were linear in the concentration range of 5-35 lg/ml. The limit of detection and limit of quantitation for experimental drugs ranged from 0.03 to 0.61 and 0.08-1.84 lg/ml respectively. ª 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).