Abstract: Adsorption, metabolism and degradation of erythromycin in freshwater prawn and tilapia aquaculture in Mekong River Delta were monitored and evaluated. They were fed practical diets medicated with erythromycin (50 and 100 mg/kg body weight for 7 days). Erythromycin residues in their muscle were determined by the Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS) method. Our study provided preliminary data for a more prudent use of erythromycin in giant freshwater prawn and tilapia, suggesting a possible withdrawal time after treatment as well as clearing away the awareness of forming and accumulating a harmful over-threshold level of derived products from parental drug during veterinary usage in aquaculture.