Sulfadimethoxine was subjected to different International Conference on Harmonisation prescribed stress conditions (hydrolysis, oxidation and photolysis). A stability-indicating high-performance liquid chromatography method was developed for analysis of the drug in the presence of its major degradation products. It involved a Knauer Eurospher C18 thermostated column at 25°C, and 9.57 mM phosphate buffer (pH adjusted to 2.0 with orthophosphoric acid)-acetonitrile (70:30 v/v) as mobile phase. The mobile phase flow rate and sample volume injected were 1.2 mL/min and 20 μL respectively. The selected wavelength for the determination was 248 nm. The method was validated for its linearity, precision, accuracy, specificity and selectivity, and then applied to the assay of sulfadimethoxine in pharmaceutical formulations. The results of the study show that sulfadimethoxine is highly sensitive to basic hydrolysis and oxidation. The mechanisms and schemas of hydrolytic, oxidative and photolytic degradation are also studied. The method developed, which separates all of the most degradation products, is simple, accurate, precise and specific. Thus, it can be applied to study the stability of veterinary preparations containing sulfadimethoxine.