A simple, accurate, and sensitive reversed-phase HPLC method was developed for the simultaneous determination of celiprolol HCl (CE) and chlorthalidone (CT). Good chromatographic separation was achieved using a 250 mm × 4.6 mm i.d., 5 μm particle size Hypurity C8 column. Mobile phase containing a mixture of methanol and 0.04 M phosphate buffer (35:65, υ/υ) at pH 7.0 was pumped at a flow rate of 1.2 mL min −1 with UV detection at 225 nm. Lisinopril dihydrate (LIS) was used as internal standard. The method showed good linearity in the ranges 0.2–20 and 0.2–10 μg mL −1 with limits of detection 0.06 and 0.04 μg mL −1 and limits of quantification 0.20 and 0.14μg mL −1 for CE and CT, respectively. The suggested method was successfully applied to the simultaneous analysis of the studied drugs in their synthetic mixture and coformulated tablet. The method was further extended to the determination of CE in biological fluids. The proposed method was also applied to the determination of the studied drugs in presence of some coadministered or related drugs such as atenolol, propranolol, acetazolamide, enalapril, nicardipine, triamterene, and hydrochlorothiazide without any interference.