Background: A tablet dosage form widely used in the treatment of cough and cold, containing phenylephrine hydrochloride, paracetamol, caffeine, and diphenhydramine hydrochloride as active pharmaceutical ingredient was selected for the development of a novel, rapid, simultaneous isocratic reversed phase-high performance liquid chromatography (RP-HPLC) method. Objective: The objective of this paper was to develop and validate a novel, rapid, simple, precise, accurate and reproducible RP-HPLC method for simultaneous estimation of phenylephrine hydrochloride, paracetamol, caffeine, diphenhydramine hydrochloride in bulk and pharmaceutical dosage form. Method: Optimized chromatographic conditions were an isocratic elution with prontosil C18-column (250×4.6 mm, 5 μ), methanol and 20mM phosphate buffer (55:45 v/v, pH 3 ) as mobile phase, flow rate 1.0 mL/min and UV detector set at λ max 220 nm. The method was validated for specificity, precision, linearity, accuracy, sensitivity, and robustness as per the International Council for Harmonization guidelines. Result: The retention times of phenylephrine hydrochloride, paracetamol, caffeine, diphenhydramine hydrochloride were found to be 2.8 min, 3.3 min, and 4.0 min and 7.3 min, respectively. This novel method was found to be rapid, simple, linear (R2> 0.99), preciserelative standard deviation < 2.0 %), accurate (recovery 98-102%), sensitive and robust. Conclusion: The proposed novel isocratic RP-HPLC method is rapid (short run time below 10min), highly selective, precise, accurate, sensitive and robust. The method was successfully applied for the simultaneous analysis of phenylephrine hydrochloride, paracetamol, caffeine, diphenhydramine hydrochloride in a pharmaceutical dosage form.