Abstract Purpose The need for sentinel lymph node biopsy (SLNB) in clinically node-negative (cN0) patients is currently questioned. Our objective was to investigate the cost-effectiveness of a preoperative noninvasive lymph node staging (NILS) model (an artificial neural network model) for predicting pathological nodal status in patients with cN0 breast cancer (BC). Methods A health-economic decision-analytic model was developed to evaluate the utility of the NILS model in reducing the proportion of cN0 patients with low predicted risk undergoing SLNB. The model used information from a national registry and published studies, and three sensitivity/specificity scenarios of the NILS model were evaluated. Subgroup analysis explored the outcomes of breast-conserving surgery (BCS) or mastectomy. The results are presented as cost (€) and quality-adjusted life years (QALYs) per 1000 patients. Results All three scenarios of the NILS model reduced total costs (–€93,244 to –€398,941 per 1000 patients). The overall health benefit allowing for the impact of SLNB complications was a net health gain (7.0–26.9 QALYs per 1000 patients). Sensitivity analyses disregarding reduced quality of life from lymphedema showed a small loss in total health benefits (0.4–4.0 QALYs per 1000 patients) because of the reduction in total life years (0.6–6.5 life years per 1000 patients) after reduced adjuvant treatment. Subgroup analyses showed greater cost reductions and QALY gains in patients undergoing BCS. Conclusion Implementing the NILS model to identify patients with low risk for nodal metastases was associated with substantial cost reductions and likely overall health gains, especially in patients undergoing BCS.