MRI does not always reflect tumor response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumor response for the subsequent clinical determination about radiotherapy or radical surgery. A training cohort and an external validation cohort were used to examine the predictive performance of SCC-ag to evaluate tumor response from teaching hospital of Harbin Medical University. The study included 397 women with SCC (age: 28-73 years). Patients consecutively enrolled between August 2008 and January 2010 (n = 205) were used as training cohort. Patients consecutively enrolled between February 2010 and May 2011 (n = 192) were used as validation cohort. A multivariate regression analysis of the data from the training cohort indicated that serum SCC-ag level is an independent factor for neo-adjuvant chemotherapy (NACT) response. Analysis of the data from the validation cohort suggested that chemotherapy response could be more accurately predicted by SCC-ag than by magnetic resonance imaging (MRI) (sensitivity (Se): 0.944 vs. 0.794; specificity (Sp): 0.727 vs. 0.636; positive predictive value (PPV): 0.869 vs. 0.806; negative predictive value (NPV): 0.873 vs. 0.618; the area under ROC curve (AUC): 0.898 vs. 0.734). Combining SCC-ag with MRI was more powerful than MRI alone (Se: 0.952 vs. 0.794; Sp: 0.833 vs. 0.636; PPV: 0.916 vs. 0.806; NPV: 0.902 vs. 0.618; AUC: 0.950 vs. 0.734). Our study indicates that serum SCC-ag level is a sensitive and reliable measure to evaluate cervical cancer response to chemotherapy. Using SCC-ag in combination with MRI findings further improves the predictive power.