Background: We have previously tested, in a laboratory setting, a novel algorithm that enables prediction of hypoglycemia. The algorithm integrates information of autonomic modulation, based on heart rate variability (HRV), and data based on a continuous glucose monitoring (CGM) device. Now, we investigate whether the algorithm is suitable for prediction of hypoglycemia and for improvement of hypoglycemic detection during normal daily activities. Methods: Twenty-one adults (13 men) with T1D prone to hypoglycemia were recruited and monitored with CGM and a Holter device while they performed normal daily activities. We used our developed algorithm (a pattern classification method) to predict spontaneous hypoglycemia based on CGM and HRV. We compared 3 different models; (i) a model containing raw data from the CGM device; (ii) a CGM∗model containing data derived from the CGM device signal; and (iii) a CGM+HRV model-combining model (ii) with HRV data. Results: A total of 12 hypoglycemic events (glucose levels < 3.9 mmol/L, 70 mg/dL) and 237 euglycemic measurements were included. For a 20-minute prediction, model (i) resulted in a ROC AUC of 0.69. If a high sensitivity of 100% was chosen, the corresponding specificity was 69%. (ii) The CGM∗model yielded a ROC AUC of 0.92 with a corresponding sensitivity of 100% and specificity of 71%. (iii) The CGM+HRV model yielded a ROC AUC of 0.96 with a corresponding sensitivity of 100% and specificity of 91%. Conclusions: Data shows that adding information of autonomic modulation to CGM measurements enables prediction and improves the detection of hypoglycemia.