INTRODUCTION: High-grade serous ovarian cancer (HGSOC) is the most aggressive and prevalent subtype of ovarian Treatment outcomes are significantly influenced by residual disease status following neoadjuvant chemotherapy (NACT). Predicting residual disease before surgery can improve patient stratification and personalized treatment strategies. METHODS: This study analyzed pre-NACT proteomic data from 20 HGSOC patients treated with NACT. Patients were categorized into two groups based on surgical outcomes: no residual disease (R0, = 14) and suboptimal residual disease (R1, = 6). From an initial set of 97 differentially expressed proteins, 18 significant proteins were selected using the BORUTA feature selection method. Three machine learning models-Random Forest (RF), Support Vector Machine (SVM), and Bootstrap Aggregation with Classification and Regression Trees (BaggedCART)-were developed and evaluated. RESULTS: The Random Forest model achieved the best performance with an AUC of 0.955, accuracy of 0.830, sensitivity of 0.904, specificity of 0.763, and F1-score of 0.839. SHapley Additive exPlanations (SHAP) analysis identified five proteins (P48637, O43491, O95302, Q96CX2, and P49189) as the most influential predictors of residual disease. These proteins, including glutathione synthetase and peptidyl-prolyl cis-trans isomerase FKBP9, are associated with chemotherapy resistance mechanisms. DISCUSSION: The findings demonstrate the potential of integrating proteomic data with machine learning techniques for predicting surgical outcomes in HGSOC. Identified protein signatures may serve as valuable biomarkers for anticipating NACT response and informing clinical decision-making, ultimately contributing to personalized patient care.