A sensitive and specific isocratic RP-HPLC was developed for quantitative estimation of Azithromycin and Ambroxol HCl tablet formulation. The developed method consisting the mobile phase K2HPO4 – pH 6.5 : Acetonitrile (68 : 32) with isocratic programming, Hypersil, BDS, C 8, column (150 mm x 4.6 mm i.d., 5μm particle size) as stationary phase with a flow rate of 1.5 mL/minute by using λmax 215nm and PDA detector. Proposed method was found to be linear in the concentration range of 100.0 to 360.0 μg/mL for Azithromycin and 15.0 to 54.0 μg/mL for Ambroxol HCl respectively, the correlation coefficient was found to be 0.999. Precision study showed that the percentage relative standard deviation was within the range of acceptable limits, and the mean recovery was found to be 100.36 % for Azithromycin and 100.24% for Ambroxol HCl. The developed method was validated for specificity by stress studies. Ambroxol HCl and Azithromycin were subjected to stress condition and products were analyzed by using photo diode array detector. It was found to be stable in milder condition of stress (0.1 M HCl, 0.1 M NaOH, 3% H2O2, at 60°C/10 minutes). The analyte peaks were well resolved from the degraded impurities