This paper is concerned with the fault isolation (FI) problem for multivariate nonlinear non-Gaussian systems by using a novel filtering method. The generalized entropy optimization principle (GEOP) is established for non-Gaussian systems with multiple faults and disturbances, where the statistic information including entropy and mean of the residual variable is maximized in the presence of the target fault as well as all the nuisance faults and disturbances, and is minimized in the absence of the target fault but in the presence of the nuisance faults and disturbances. Different from the existing results where the output is measurable for feedback, the fault isolation filter is designed and driven by the joint output stochastic distributions rather than its deterministic value. The error dynamics is represented by a multivariate nonlinear non-Gaussian system, for which new recursive relationships are proposed to formulate the joint probability density functions (JPDFs) of the residual variable in terms of the JPDFs of the noises and the faults. Finally, a simulation example is given to demonstrate the effectiveness of the proposed multivariate FI algorithms. (C) 2009 Elsevier Ltd. All rights reserved.