In this paper, an innovative controller is proposed to compensate for both the nonlinear hysteresis and the vibration dynamics effects of a nanopositioning stage driven by piezoelectric actuators. With the increasing of operating bandwidth and range, large positioning errors are produced because of the hysteresis, vibration, external disturbance and noise, as well as uncompleted modeled dynamic errors. The main contribution of this work is that an adaptive approach based on iterative learning control (ILC) combined with discrete-time variable structure control is proposed for the disturbance estimation and disturbance rejection. The discrete-time sliding mode controller is applied to corporate with ILC, which is effective to compensate for nonrepeating disturbance. In addition, the proposed control algorithm is applied to experimentally validate the effectiveness of enhancing the performance in positioning control of a nanopositioning stage.