An anoxic-oxic activated sludge process (AOASP) was carried out to treat shortchain nonylphenol polyethoxylates (SCNPEOs). The operation parameters, including temperature, hydraulic retention time (HRT) and solids retention time (SRT), were optimized by an L9(33) orthogonal experiment. Effluent concentrations and effluent removal efficiency of each SCNPEOs component were selected as the evaluation index for the orthogonal experiment. The optimum operation parameters were achieved as temperature of 40 °C, HRT of 12 hr and SRT of 15 d. The largest influence factor to the degradation of mixed nonylphenol diethoxylate (M-NP2EO) was temperature, followed by HRT and SRT. The molecular biology analysis results supported the conclusions of orthogonal experiment. The highest ratio of Proteobacteria achieved 40% in anoxic tank and 50% in oxic tank. These results showed that the AOASP might be an effective method to degrade SCNPEOs