A novel stability-indicating reverse-phase high-performance liquid chromatographic (HPLC) method has been developed for quantitative determination of Fosamprenavir Calcium, HIV-1 protease inhibitor. Chromatographic separation was achieved using an YMC Pack ODS AQ (150 mm × 4.6 mm × 3.0 μm) HPLC column in isocratic mode employing 0.05 M Potassium dihydrogen orthophosphate monohydrate (pH 6.8) buffer and Acetonitrile in the ratio 60:40 (v/v) with a flow rate of 0.8 mL min(-1). Detector wavelength was monitored at 265 nm and column temperature was maintained at 40 °C. Fosamprenavir calcium was exposed to thermal, photolytic, humidity, water, acid, base and oxidative stress conditions. Considerable degradation of the drug substance was found to occur under acid, base and oxidative stress conditions. Peak homogeneity data of Fosamprenavir Calcium obtained by photodiode array detection demonstrated the specificity of the method in the presence of degradants. The degradation products were well resolved from the main peak of Fosamprenavir, indicating that the method is specific and stability-indicating. The HPLC method was validated as per International Conference on Harmonization guidelines with respect to specificity, precision, linearity, accuracy and robustness. Regression analysis showed a correlation coefficient value greater than 0.999. The accuracy of the method was established based on the recovery obtained for Fosamprenavir Calcium.