A rapid and simple reversed-phase high performance liquid chromatographic (HPLC) method has been developed and validated for the routine analysis of adefovir dipivoxil and its degradation products (adefovir and mono-POM PMEA). The influences of pH, concentrations of buffer and acetonitrile to the retention of adefovir dipivoxil and its related substances have been investigated. The separation between adefovir dipivoxil and its degradation products was performed on a CN-3 column and the quantitation was achieved with UV detection at 260 nm. A mixture of acetonitrile and 25 mmol/L phosphate buffer (to adjust the pH to 4.0 with phosphoric acid) (33:67, v/v) was used as the mobile phase for isocratic elution with a flow rate of 1.0 mL/min. This method demonstrated the baseline separation of the three analytes free of interference within 8 min. The calibration curves were linear (r = 0.9999 and 0.9998) in the concentration range of 1.861-181.7 mg/L and 2.018-197.2 mg/L of adefovir dipivoxil and adefovir respectively. The average recoveries of adefovir dipivoxil and adefovir were 99.5%-101.0% and 99.1%-99.6% respectively, and the relative standard deviation was less than 1.0%. The minimum detectable quantity of adefovir was 1 ng (S/N = 3). The method is simple, reproducible and can be applied to the determination of adefovir dipivoxil and its degradation products simultaneously.