Objective: To assess the role of HE4 (Human epidydimal protein 4) marker as predictor of response to platinum based chemotherapy. Methods: In the current observational prospective study, 35 patients affected by High Grade Serous Ovarian Cancer (HGSOC) were enrolled; among these, 17 patients were platinum sensitive, while 18 were platinum resistant. HE4 levels were measured before surgery, at the III and at the VI cycle of chemotherapy. Results: The reduction of 50% or more of HE4 levels at the III cycle of chemotherapy showed a specificity of 100% and a sensitivity of 27%. The negativization (<70 pmol/L) of HE4 at the III cycle of chemotherapy showed a specificity of 100%, with a sensitivity of 39%, in predicting chemotherapy response, while the same parameter at the VI cycle showed a specificity of 82% and a sensitivity of 67%. Moreover the ROC analysis identified the HE4 cut-off value of 62.79 pmol/L as the best cut-off in predicting chemotherapy response, with a sensitivity of 72% and a specificity of 88% at the III cycle. Discussion: Our results suggest that HE4 levels during first-line chemotherapy, in particular at the III cycle, could predict chemotherapy response in HGSOC patients.