Abstract: On the basis of considering multi energy interaction of cross-regional integrated energy system an optimal operation strategy considering multi-scale demand response was proposed. Firstly, in allusion to the response time a multi-scale demand response was established, including invitation demand response and real-time demand response, where the invitation was divided into 24 hours before the day and 4 hours within the day, and. the real-time response is 15 minutes within the day. Secondly, considering different response proportions of various electric, thermal, cool and gas loads under different time-scales, the load demand response models with different proportions under multiple time scales were constructed. Finally, a cross-regional integrated energy system operation model, in which the demand response information was issued by cross-regional energy service providers, the load aggregators participated in demand response and adjusted the time and the way of energy usage, was built. By use of the post-optimization load curves the cross-regional energy service providers adjusted the output of generating units inside the system and the power interaction among systems. Results of computing example verify the reasonableness and effectiveness of the proposed operation strategy, and using the proposed operation strategy both the profit of each regional integrated energy system and the comprehensive benefits of the load aggregators are somewhat improved.