Erythromycin mycelial dreg (EMD) is a bio-fermentation residue of the pharmaceutical industry that may be used as a nutrient resource. However, the contaminants present in EMD need to be considered and controlled at an acceptable level prior to utilization. In this study, heat-activated persulfate (PS) oxidation of EMD was developed to degrade the residual erythromycin (ERY) and inactivate the ERY-resistant genes. The effects of temperature, initial PS concentration, and pH on the removal of ERY in EMD were studied. The results revealed that 99.0% ERY was degraded by 25 g PS/kg EMD under 80 degrees C within 120 min. The apparent rate constant (k(app)) in the acidic condition was higher than that in the alkaline condition. The contribution of sulfate radical (SO4 center dot-) and hydroxyl radical (HO center dot) on ERY removal in EMD was found to be 36.8% and 29.4%, respectively. Six intermediate products (IPs) of ERY were clarified, and total organic carbon (TOC) was efficiently reduced by 99.4%. Finally, the detected ERY-resistant genes ere(B), erm(A), and erm(B) obviously presented a reduction during the heat-activated PS oxidation process.