OBJECTIVE: Delirium is an important syndrome found in patients in the intensive care unit (ICU), however, it is usually under-recognized during treatment. This study was performed to investigate whether delirious patients can be successfully distinguished from non-delirious patients by using heart rate variability (HRV) and machine learning. APPROACH: Electrocardiography data of 140 patients was acquired during daily ICU care, and HRV data were analyzed. Delirium, including its type, severity, and etiologies, was evaluated daily by trained psychiatrists. HRV data and various machine learning algorithms including linear support vector machine (SVM), SVM with radial basis function (RBF) kernels, linear extreme learning machine (ELM), ELM with RBF kernels, linear discriminant analysis, and quadratic discriminant analysis were utilized to distinguish delirium patients from non-delirium patients. MAIN RESULTS: HRV data of 4797 ECGs were included, and 39 patients had delirium at least once during their ICU stay. The maximum classification accuracy was acquired using SVM with RBF kernels. Our prediction method based on HRV with machine learning was comparable to previous delirium prediction models using massive amounts of clinical information. SIGNIFICANCE: Our results show that autonomic alterations could be a significant feature of patients with delirium in the ICU, suggesting the potential for the automatic prediction and early detection of delirium based on HRV with machine learning.