Radiogenomics investigates the relationship between imaging phenotypes and genetic expression. Breast cancer is a heterogeneous disease that manifests complex genetic changes and various prognosis and treatment response. We investigate the value of machine learning approaches to radiogenomics using low-dose perfusion computed tomography (CT) to predict prognostic biomarkers and molecular subtypes of invasive breast cancer. This prospective study enrolled a total of 723 cases involving 241 patients with invasive breast cancer. The 18 CT parameters of cancers were analyzed using 5 machine learning models to predict lymph node status, tumor grade, tumor size, hormone receptors, HER2, Ki67, and the molecular subtypes. The random forest model was the best model in terms of accuracy and the area under the receiver-operating characteristic curve (AUC). On average, the random forest model had 13% higher accuracy and 0.17 higher AUC than the logistic regression. The most important CT parameters in the random forest model for prediction were peak enhancement intensity (Hounsfield units), time to peak (seconds), blood volume permeability (mL/100 g), and perfusion of tumor (mL/min per 100 mL). Machine learning approaches to radiogenomics using low-dose perfusion breast CT is a useful noninvasive tool for predicting prognostic biomarkers and molecular subtypes of invasive breast cancer.