The purpose of this study was to validate the use of artificial neural network (ANN) models for predicting quality of life (QOL) after breast cancer surgery and to compare the predictive capability of ANNs with that of linear regression (LR) models. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its supplementary breast cancer measure were completed by 402 breast cancer patients at baseline and at 2 years postoperatively. The accuracy of the system models were evaluated in terms of mean square error (MSE) and mean absolute percentage error (MAPE). A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and to rank the variables in order of importance. Compared to the LR model, the ANN model generally had smaller MSE and MAPE values in both the training and testing datasets. Most ANN models had MAPE values ranging from 4.70 to 19.96 %, and most had high prediction accuracy. The ANN model also outperformed the LR model in terms of prediction accuracy. According to global sensitivity analysis, pre-operative functional status was the best predictor of QOL after surgery. Compared with the conventional LR model, the ANN model in the study was more accurate for predicting patient-reported QOL and had higher overall performance indices. Further refinements are expected to obtain sufficient performance improvements for its routine use in clinical practice as an adjunctive decision-making tool.