An internal model-based neural network control is proposed for unknown non-affine discrete-time multi-input multi-output (MIMO) processes in nonlinear state space form under model mismatch and disturbances. Based on the neural state-space model built for an unknown nonlinear MIMO state space process, an approximate internal model and approximate decoupling controllers are derived simultaneously. Thus, the learning of the inverse process dynamics is not required. A neural network model-based extended Kalman observer is used to estimate the states of a nonlinear process as not all states are accessible. The proposed neural internal model control can work for open-loop unstable processes with its closed-loop stability derived analytically. The application to a distributed thermal process shows the effectiveness of the proposed approach for suppressing nonlinear coupling and external disturbances and its feasibility for the control of unknown non-affine nonlinear discrete-time MIMO state space processes. (C) 2009 Elsevier Ltd. All rights reserved.