This paper proposes a novel data-based adaptive predictive frequency control method for multi-area power systems with unknown and time-varying inertia. Firstly, a data-based representation is built and updated at each instant based on behavioural system theory by using historical input–output data, where a moving horizon estimation method is used to deal with the unknown time-varying inertia issue adaptively. Then, the optimal frequency control signal is computed by solving an optimization problem under the framework of data-based predictive control. Simulation results on a power system with three control areas demonstrate the effectiveness of the proposed method.