A simple, rapid, precise, and accurate stability-indicating, reversed phase (RP) HPLC assay method was developed and validated for simultaneous estimation of Lamivudine (3TC) and Stavudine (d4T) in bulk drugs and commercial tablets. The method has shown adequate separation of 3TC and d4T from their degradation products. Separation was achieved on a Kromasil C8 (250mm×4.6mm i.d; 5 μm) column at a detection wavelength of 265nm, using a mobile phase consisting of acetonitrile–0.02M ammonium acetate buffer (pH 4.5) in a gradient elution mode at a flow rate of 1 ml/min. The retention times for lamivudine and stavudine were found to be 13.66 and 16.51 min respectively Lamivudine (3TC), stavudine (d4T) and their combination drug product were subjected to acid, base and neutral hydrolysis, oxidation, thermal and photolytic stress conditions and the stressed samples were analyzed by the proposed method. Validation of the method was carried out as per ICH guidelines. Quantitation was achieved with UV detection at 265 nm based on peak area with linear calibration curves at concentration ranges 2.5-50μg/ml for 3TC and 0.5-10μg/ml for d4T (R2 > 0.9999 for both drugs). The limits of detection were 0.82 μg/ml and 0.33 μg/ml for lamivudine and stavudine, respectively. The method was found to be specific and stability indicating as no interfering peaks of degradants and excipients were observed. The proposed method is hence suitable for application in quality-control laboratories for quantitative analysis of both the drugs individually and in combination dosage forms, since it is simple and rapid with good accuracy and precision