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In this paper the disturbance rejection problem is investigated for a class of multiple-input-multiple-output (MIMO) nonlinear systems with neutral uncertainty via disturbance-observer-based control (DOBC) approach. The unknown external disturbances are supposed to be generated by an exogenous system, which can represent the constant and harmonic signals. The disturbance observer design is separated from the controller design by using of the separation principle. A new design scheme is presented for the reduced-order disturbance observer via convex optimization. By integrating the disturbance observer with conventional controller, the disturbances can be rejected. Thus, the stability can be guaranteed and performance can be improved. Finally, a numerical example is given to demonstrate the effectiveness and robustness of the approach.